Pharmaceutical Compositions

ABSTRACT

Disclosed herein are pharmaceutical powder compositions, methods of making such compositions, and uses thereof.

CROSS-REFERENCE

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 62/371,298, filed Aug. 5, 2016, which isincorporated herein by reference in its entirety.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications disclosed herein areincorporated by reference to the same extent as if each individualpublication, patent, or patent application was specifically andindividually indicated to be incorporated by reference. In the event ofa conflict between a term disclosed herein and a term in an incorporatedreference, the term herein controls.

BRIEF SUMMARY

The inventive embodiments provided in this Brief Summary are meant to beillustrative only and to provide an overview of selective embodimentsdisclosed herein. The Brief Summary, being illustrative and selective,does not limit the scope of any claim, does not provide the entire scopeof inventive embodiments disclosed or contemplated herein, and shouldnot be construed as limiting or constraining the scope of thisdisclosure or any claimed inventive embodiment.

In some cases, the present disclosure provides for an intranasalpharmaceutical powder composition comprising particles that comprise anactive agent and at least one member selected from the group consistingof a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol,and any combination thereof, wherein: at least about 20 percent byweight of the active agent in the particles is amorphous as determinedby X-ray diffraction; when the active agent has a crystalline form, asolubility of the active agent in a crystalline form in an aqueousliquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at atemperature of 37±0.5° C.; the particles have an average particle sizeof about 10 microns to about 300 microns, as measured by laserdiffraction; and when the intranasal pharmaceutical powder compositionis administered, a pharmacokinetic parameter of the active agentimproves by at least about 15%, compared to a corresponding compositionthat comprises the active agent in a crystalline form when intranasallyadministered, as measured by a same method. In some instances, thepharmaceutical powder composition comprises the active agent, thethickening agent, the carrier, and the sugar alcohol. In some instances,the pharmaceutical powder composition further comprises particles thatcomprise the active agent and are free from the thickening agent, thecarrier, or a combination thereof. In some instances, the active agentis a non-peptide/non-protein drug. In some instances, the active agentis selected from the group consisting of an ergot alkaloid,5-hydroxytryptaminel (5-HT1) receptor agonist, CGRP antagonist, NK-1receptor antagonist, antihistamine, antiemetic agent, decongestant,opioid receptor agonist, antibiotic, antifungal agent, sulfa drug,antituberculosis drug, antimicrobial agent, antiviral agent, hypnoticsedative, antiepileptic agent, narcotic analgesic, nonnarcoticanalgesic, sedative drug, psychotherapeutic agent, muscle relaxant,antiallergic agent, anti-rheumatic drug, cardiotonic drug,antiarrhythmic agent, antihypertensive agent, diuretic agent, coronaryvasodilator, antidementia drug, brain activator, brain circulationameliorating agent, antiparkinsonian agent, antihyperlipidemic drug,antiulcer drug, obesity drug, diabetic drug, hemostatic drug,antithrombotic agent, migraine drug, antitussive drug, expectorant,respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidalantiinflammatory agent, antipodagric, therapeutic agent for urinarydisease, drug for improving sexual function, agent for the uterus,steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavymetal toxification, quit smoking agent, antianaphylactic agent,antitumor agent, immunostimulator, immunosuppressive drug, and anycombination thereof. In some instances, the active agent is selectedfrom the group consisting of didanosine, zidovudine, lamivudine,acyatazanavir, nelfenavir, sanilvudine, emtricitabine,polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir,peramivir, laninamivir, favipiravir, amantadine, amphotericin B,miconazole, fluconazole, itraconazole, ketoconazole, ketamine,pentobarbital sodium, thiopental, amopentobarbital, hexobarbital,lidocaine, triazolam, zopiclone, zolpidem, eszopiclone, etizolam,clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam,flunitrazepam, diazepam, chlordiazepoxide HCl, alprazolam, lorazepam,ethyl loflazepate, bromazepam, rilmazafone, chloral hydrate,carbamazepine, clonazepam, zonisamide, sodium valproate, phenytoin,phenobarbital, primidone, gabapentin, opium, morphine, ethylmorphine,oxycodone, hydrocodone, codeine, dihydrocodeine, fentanyl, remifentanil,droperidol, levorphanol, methadone, meperidine, pethidine,buprenorphine, butorphanol, tramadol, tapentadol, nalfurafine,pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine,levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine,dihydroergotamine (DHE), sumatriptan, eletriptan, zolmitriptan,rizatriptan, naratriptan, almotriptan, frovatriptan, avitriptan,lasmiditan, olcegepant, telcagepant, donepezil, suxamethonium,pancuronium, sildenafil, vardenafil, apomorphine, tadalafil, atropine,scopolamine, homatropine methylbromide, chlorpromazine, digitoxin,levomepromazine, thioridazine, acepromazine, digoxin, methyldigoxin,isosorbide, nitroglycerin, quinidine, disopyramide, dopamine,dobutamine, epinephrine, etilefrine, norepinephrine, phenylephrine,dimorpholamine, doxapram, naloxone, flumazenil, tipepidine,dextromethorphan, ambroxol, bromhexine, salbutamol, terbutaline,procaterol, theophylline, ephedrine, sodium cromoglycate, ketotifen,oxatomide, tranilast, granisetron, azasetron, ramosetron, tropisetron,indisetron, palonosetron, cisapride, domperidone, metoclopramide,trimebutine, loperamide, mefenamic acid, indomethacin, sulindac,ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac,tiaprofenic acid, tiaramide, carbazochrome sulfonic acid, tranexamicacid, pralidoxime iodide methyl, progesterone, testosterone,dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine,leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone,risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir,famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine,idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin,carmustine, beraprost sodium, and any combination thereof. In someinstances, the active agent is a peptide or a peptide-related compound,wherein the peptide or peptide-related compound has a molecular weightof 50,000 Daltons or less. In some instances, the active agent isselected from the group consisting of insulin, human growth hormone,calcitonin, glucagon, parathyroid hormone, parathyroid hormone (1-34),glucagon-like peptide-1, interferon, interleukin, erythropoietin,luteinizing hormone-releasing hormone, somatostatin, vasopressin,oxytocin, enkephalin, adrenocorticotropic hormone, growthhormone-releasing hormone, granulocyte colony formation-stimulatingfactor, parathyroid hormone, thyroid-stimulating hormone-releasinghormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitorypolypeptide (GIP), C-peptide, cyclosporine, FK-506, octreotide,carperitide, pramlintide, lanreotide, eptifibatide, albiglutide,pasireotide, teriparatide, exenatide, liraglutide, emfuvirtide,ziconotide, ecallantide, mifamurtide, nesiritide, peglinesatide,afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide,cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide,a peptide analog thereof, and any combination thereof. In someinstances, the active agent is a small molecule drug. In some instances,the active agent is an anti-migraine drug. In some instances, the activeagent is an ergot alkaloid. In some instances, the active agent is DHEor a pharmaceutically acceptable salt thereof. In some instances, theactive agent is DHE mesylate. In some instances, the active agent isindomethacin, midazolam, phenobarbital, or a pharmaceutically acceptablesalt of any of the foregoing. In some instances, the active agent has anaverage particle size of about 5 microns or larger. In some instances,the particles have an average particle size of from about 15 to about100 μm, or about 15-200 microns, as measured by laser diffraction. Insome instances, the particles have an average particle size of fromabout 20 to about 50 μm, or about 50-150 microns, as measured by laserdiffraction. In some instances, the particles are spray dried,freeze-dried, or melt-extruded. In some instances, the active agent isspray dried onto the carrier, the thickening agent, or a combinationthereof. In some instances, the solubility is measured at a pH rangingfrom about 6.8 to about 7.4. In some instances, the particles comprisethe carrier that is at least partially water insoluble at 37±0.5° C. Insome instances, the water insolubility is measured at a pH ranging fromabout 6.8 to about 7.4. In some instances, the particles furthercomprise the thickening agent, and wherein the carrier has lower watersolubility than that of the thickening agent. In some instances, theparticles comprise the carrier that is at least partially adhesive tomucus. In some instances, the particles comprise the carrier thatcomprises a polysaccharide, an oligosaccharide, or any combinationthereof. In some instances, the carrier comprises microcrystallinecellulose, ethyl cellulose, cellulose acetate, cellulose acetatebutyrate, cellulose acetate propionate, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, starch, chitosan, βcyclodextrin, or any combination thereof. In some instances, theparticles comprise the carrier that has an average particle size of fromabout 5 to about 100 μm, as measured by laser diffraction. In someinstances, the carrier has an average particle size of about 20 or about23 μm, as measured by laser diffraction. In some instances, theparticles comprise the thickening agent that is at least partially watersoluble at 37±0.5° C. In some instances, the water solubility ismeasured at a pH ranging from about 6.8 to about 7.4. In some instances,the particles further comprise the carrier, and wherein the thickeningagent has higher water solubility than that of the carrier. In someinstances, the particles comprise the thickening agent that binds to theactive agent. In some instances, the particles further comprise thecarrier, and wherein the thickening agent binds to the active agent andthe carrier. In some instances, the particles comprise the thickeningagent that comprises a polysaccharide. In some instances, the thickeningagent comprises hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, methyl cellulose, carboxymethylcellulose calcium, sodiumcarboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum,locust bean gum, gum tragacanth, starch, carbopols, methylcellulose,polyvinylpyrrolidone, or any combination thereof. In some instances, theparticles comprise the thickening agent and have an average particlesize of from about 10 to about 50 μm, about 15 to about 200 microns, asmeasured by laser diffraction. In some instances, the particles have anaverage particle size of about 15 μm, or about 50 to 150 microns, asmeasured by laser diffraction. In some instances, the particles comprisethe thickening agent, the sugar alcohol, and the carrier and have anaverage particle size of from about 10 to about 50 μm, or about 15 to200 microns, as measured by laser diffraction. In some instances, theparticles have an average particle size of about 20 μm, or about 50 to150 microns, as measured by laser diffraction. In some instances, thepharmaceutical powder composition further comprises a fluidizing agent.In some instances, the fluidizing agent comprises a calcium phosphate.In some instances, the calcium phosphate comprises tribasic calciumphosphate. In some instances, when the intranasal pharmaceutical powdercomposition is administered to the subject, a pharmacokinetic parameterof the active agent improves by at least about: 20%, 25%, 30%, 40%, 45%,50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, or 500%,compared to a corresponding composition that comprises the active agentin a crystalline form when administered. In some instances, the improvedpharmacokinetic parameter comprises a greater relative bioavailabilityfrom 0 min to 15 min (rBA_(0-15min)), a greater relative bioavailabilityfrom 0 min to 30 min (rBA_(0-30min)), a greater relative bioavailabilityfrom 0 min to 60 min (rBA_(0-60min)), or any combination thereof. Insome instances, the improved pharmacokinetic parameter comprises anaverage rBA_(0-15min), and the improvement is at least about 100%, e.g.,at least about 115% or 150%. In some instances, the averagerBA_(0-15min) is about 150% to 1500% in serum of the subject. In someinstances, the improved pharmacokinetic parameter comprises an averagerBA_(0-30min), and the improvement is at least about 80%, e.g., at leastabout 115%. In some instances, the improved pharmacokinetic parametercomprises an average rBA_(0-60min), and the improvement is at least100%, e.g., at least about 115%. In some instances, the improvedpharmacokinetic parameter comprises a higher maximum blood concentration(C_(max)). In some instances, the improved pharmacokinetic parametercomprises a shorter time to reach maximum blood concentration (T_(max)).In some instances, the improved pharmacokinetic parameter comprises anincreased area under the curve (AUC) for blood concentration-timeprofile. In some instances, the pharmaceutical powder compositionfurther comprises an additional active agent. In some instances, theadditional active agent comprises caffeine, which is amorphous,crystalline, at least 20% of amorphous by weight of the caffeine, or anycombination thereof. In some instances, at least about: 25%, 30%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% by weightof the active agent is amorphous. In some instances, the pharmaceuticalpowder composition retains at least about: 80%, 85%, 90%, or 95% byweight of the active agent in a closed container after a period of atleast about: 30, 60, 120, 180, 360, 720, or 1080 days. In someinstances, the container is kept at about 20° C. to about 40° C. at astandard atmosphere pressure with a relative humidity of about 50% toabout 75%. In some instances, the container is kept at about 25° C. at astandard atmosphere pressure with a relative humidity of about 50%. Insome instances, the crystalline form comprises a polymorph.

In some instances, the intranasal pharmaceutical powder compositioncomprises indomethacin or a pharmaceutically acceptable salt thereof,microcrystalline cellulose, and mannitol. In some instances, theintranasal pharmaceutical powder composition comprises indomethacin or apharmaceutically acceptable salt thereof, microcrystalline cellulose,and tribasic calcium phosphate. In some instances, the indomethacin or apharmaceutically acceptable salt thereof is in a freeze-dried form,amorphous, or a combination thereof. In some instances, themicrocrystalline cellulose comprises a first microcrystalline cellulosethat has an average particle size of about 20-23 μm and a secondmicrocrystalline cellulose has an average particle size of about 50 μm.In some instances, the pharmaceutical powder composition comprises:indomethacin or a pharmaceutically acceptable salt thereof, e.g.,freeze-dried and/or amorphous, which is present in about 1-15% of atotal weight of the pharmaceutical powder composition; a firstmicrocrystalline cellulose that is present in about 70-95% of the totalweight of the pharmaceutical powder composition, wherein the firstmicrocrystalline cellulose has an average particle size of about 20-23μm; a second microcrystalline cellulose that is present in about 1-20%of the total weight of the pharmaceutical powder composition, whereinthe second microcrystalline cellulose has an average particle size ofabout 50 μm; and tribasic calcium phosphate that is present in about0.5-5% of the total weight of the pharmaceutical powder composition. Insome instances, the pharmaceutical powder composition comprises:indomethacin or a pharmaceutically acceptable salt thereof, e.g.,freeze-dried and/or amorphous, which is present in about 5% of a totalweight of the pharmaceutical powder composition; a firstmicrocrystalline cellulose that is present in about 84% of the totalweight of the pharmaceutical powder composition, wherein the firstmicrocrystalline cellulose has an average particle size of about 20-23μm; a second microcrystalline cellulose that is present in about 10% ofthe total weight of the pharmaceutical powder composition, wherein thesecond microcrystalline cellulose has an average particle size of about50 μm; and tribasic calcium phosphate that is present in about 1% of thetotal weight of the pharmaceutical powder composition. In someinstances, the pharmaceutical powder composition comprises: about 0.5-5mg of indomethacin or a pharmaceutically acceptable salt thereof, e.g.,freeze-dried and/or amorphous; about 10-18 mg of microcrystallinecellulose that has an average particle size of about 20-23 μm; about1-10 mg of microcrystalline cellulose that has an average particle sizeof about 50 μm; and about 0.1-2 mg of tribasic calcium phosphate. Insome instances, the pharmaceutical powder composition comprises: about 1mg of indomethacin or a pharmaceutically acceptable salt thereof, e.g.,freeze-dried and/or amorphous; about 16.8 mg of microcrystallinecellulose that has an average particle size of about 20-23 μm; about 2mg of microcrystalline cellulose that has an average particle size ofabout 50 μm; and about 0.2 mg of tribasic calcium phosphate.

In some instances, the intranasal pharmaceutical powder compositioncomprises testosterone or a pharmaceutically acceptable salt thereof,microcrystalline cellulose, and mannitol. In some instances, theintranasal pharmaceutical powder composition comprises testosterone or apharmaceutically acceptable salt thereof, microcrystalline cellulose,and tribasic calcium phosphate. In some instances, the indomethacin or apharmaceutically acceptable salt thereof is a freeze-dried form,amorphous, or a combination thereof. In some instances, themicrocrystalline cellulose comprises a first microcrystalline cellulosethat has an average particle size of about 20-23 μm and a secondmicrocrystalline cellulose has an average particle size of about 50 μm.In some instances, wherein the pharmaceutical powder compositioncomprises: testosterone or a pharmaceutically acceptable salt thereof,e.g., freeze-dried and/or amorphous, which is present in about 1-20% ofa total weight of the pharmaceutical powder composition; a firstmicrocrystalline cellulose that is present in about 70-95% of the totalweight of the pharmaceutical powder composition, wherein the firstmicrocrystalline cellulose has an average particle size of about 20-23μm; a second microcrystalline cellulose that is present in about 1-20%of the total weight of the pharmaceutical powder composition, whereinthe second microcrystalline cellulose has an average particle size ofabout 50 μm; and tribasic calcium phosphate that is present in about0.5-5% of the total weight of the pharmaceutical powder composition. Insome instances, the pharmaceutical powder composition comprises:testosterone or a pharmaceutically acceptable salt thereof, e.g.,freeze-dried and/or amorphous, which is present in about 10% of a totalweight of the pharmaceutical powder composition; a firstmicrocrystalline cellulose that is present in about 79% of the totalweight of the pharmaceutical powder composition, wherein the firstmicrocrystalline cellulose has an average particle size of about 20-23μm; a second microcrystalline cellulose that is present in about 10% ofthe total weight of the pharmaceutical powder composition, wherein thesecond microcrystalline cellulose has an average particle size of about50 μm; and tribasic calcium phosphate that is present in about 1% of thetotal weight of the pharmaceutical powder composition. In someinstances, the pharmaceutical powder composition comprises: about 1-10mg of testosterone or a pharmaceutically acceptable salt thereof, e.g.,freeze-dried and/or amorphous; about 10-18 mg of microcrystallinecellulose that has an average particle size of about 20-23 μm; about1-10 mg of microcrystalline cellulose that has an average particle sizeof about 50 μm; and about 0.1-2 mg of tribasic calcium phosphate. Insome instances, wherein the pharmaceutical powder composition comprises:about 2 mg of testosterone or a pharmaceutically acceptable saltthereof, e.g., freeze-dried and/or amorphous; about 15.8 mg ofmicrocrystalline cellulose that has an average particle size of about20-23 μm; about 2 mg of microcrystalline cellulose that has an averageparticle size of about 50 μm; and about 0.2 mg of tribasic calciumphosphate.

In some cases, the present disclosure provides for a method, comprisingintranasally administering to a subject a pharmaceutical powdercomposition comprising particles that comprise an active agent and atleast one member selected from the group consisting of a thickeningagent, a carrier, a pH adjusting agent, a sugar alcohol, and anycombination thereof, wherein at least about 20 percent by weight of theactive agent in the particles is amorphous as determined by X-raydiffraction; when the active agent has a crystalline form, a solubilityof the active agent in a crystalline form ranges from about 0.1 μg/mL toabout 1 mg/mL in water at a temperature of 37±0.5° C. at a pH rangingfrom about 6.8 to about 7.4; the particles have an average particle sizeof about 10 microns to about 300 microns, as measured by laserdiffraction; and the intranasal administration of the pharmaceuticalpowder composition improves a pharmacokinetic parameter of the activeagent by at least about 15%, when compared to an intranasaladministration of a corresponding composition that comprises the activeagent in a crystalline form, as measured by a same method. In someinstances, the pharmaceutical powder composition comprises the activeagent, the thickening agent, the carrier, and the sugar alcohol. In someinstances, the pharmaceutical powder composition further comprisesparticles that comprise the active agent and are free from thethickening agent, the carrier, or a combination thereof. In someinstances, the active agent is a non-peptide/non-protein drug. In someinstances, the active agent is selected from the group consisting ofergot alkaloid, 5-hydroxytryptaminel (5-HT1) receptor agonist, CGRPantagonist, NK-1 receptor antagonist, antihistamine, antiemetic agent,decongestant, opioid receptor agonist, antibiotic, antifungal agent,sulfa drug, antituberculosis drug, antimicrobial agent, antiviral agent,hypnotic sedative, antiepileptic agent, narcotic analgesic, nonnarcoticanalgesic, sedative drug, psychotherapeutic agent, muscle relaxant,antiallergic agent, anti-rheumatic drug, cardiotonic drug,antiarrhythmic agent, antihypertensive agent, diuretic agent, coronaryvasodilator, antidementia drug, brain activator, brain circulationameliorating agent, antiparkinsonian agent, antihyperlipidemic drug,antiulcer drug, obesity drug, diabetic drug, hemostatic drug,antithrombotic agent, migraine drug, antitussive drug, expectorant,respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidalantiinflammatory agent, antipodagric, therapeutic agent for urinarydisease, drug for improving sexual function, agent for the uterus,steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavymetal toxification, quit smoking agent, antianaphylactic agent,antitumor agent, immunostimulator, immunosuppressive drug, and anycombination thereof. In some instances, the active agent is selectedfrom the group consisting of didanosine, zidovudine, lamivudine,acyatazanavir, nelfenavir, sanilvudine, emtricitabine,polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir,peramivir, laninamivir, favipiravir, amantadine, amphotericin B,miconazole, fluconazole, itraconazole, ketoconazole, ketamine,pentobarbital sodium, thiopental, amopentobarbital, hexobarbital,lidocaine, triazolam, zopiclone, zolpidem, eszopiclone, etizolam,clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam,flunitrazepam, diazepam, chlordiazepoxide HCl, alprazolam, lorazepam,ethyl loflazepate, bromazepam, rilmazafone, chloral hydrate,carbamazepine, clonazepam, zonisamide, sodium valproate, phenytoin,phenobarbital, primidone, gabapentin, opium, morphine, ethylmorphine,oxycodone, hydrocodone, codeine, dihydrocodeine, fentanyl, remifentanil,droperidol, levorphanol, methadone, meperidine, pethidine,buprenorphine, butorphanol, tramadol, tapentadol, nalfurafine,pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine,levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine,dihydroergotamine, sumatriptan, eletriptan, zolmitriptan, rizatriptan,naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan,olcegepant, telcagepant, donepezil, suxamethonium, pancuronium,sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine,homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine,thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide,nitroglycerin, quinidine, disopyramide, dopamine, dobutamine,epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine,doxapram, naloxone, flumazenil, tipepidine, dextromethorphan, ambroxol,bromhexine, salbutamol, terbutaline, procaterol, theophylline,ephedrine, sodium cromoglycate, ketotifen, oxatomide, tranilast,granisetron, azasetron, ramosetron, tropisetron, indisetron,palonosetron, cisapride, domperidone, metoclopramide, trimebutine,loperamide, mefenamic acid, indomethacin, sulindac, ibuprofen,ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenicacid, tiaramide, carbazochrome sulfonic acid, tranexamic acid,pralidoxime iodide methyl, progesterone, testosterone,dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine,leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone,risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir,famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine,idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin,carmustin, beraprost sodium, and any combination thereof. In someinstances, the active agent is a peptide or a peptide-related compound,wherein the peptide or peptide-related compound has a molecular weightof 50,000 Daltons or less. In some instances, the active agent isselected from the group consisting of insulin, human growth hormone,calcitonin, glucagon, parathyroid hormone, parathyroid hormone (1-34),glucagon-like peptide-1, interferon, interleukin, erythropoietin,luteinizing hormone-releasing hormone, somatostatin, vasopressin,oxytocin, enkephalin, adrenocorticotropic hormone, growthhormone-releasing hormone, granulocyte colony formation-stimulatingfactor, parathyroid hormone, thyroid-stimulating hormone-releasinghormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitorypolypeptide (GIP), C-peptide, cyclosporine, FK-506, octreotide,carperitide, pramlintide, lanreotide, eptifibatide, albiglutide,pasireotide, teriparatide, exenatide, liraglutide, emfuvirtide,ziconotide, ecallantide, mifamurtide, nesiritide, peglinesatide,afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide,cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide,a peptide analog thereof, and any combination thereof. In someinstances, the active agent is a small molecule drug. In some instances,the active agent is an anti-migraine drug. In some instances, the activeagent is an ergot alkaloid. In some instances, the active agent isdihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof.In some instances, the active agent is dihydroergotamine mesylate. Insome instances, the active agent is indomethacin, midazolam,phenobarbital, or a pharmaceutically acceptable salt of any of theforegoing. In some instances, the active agent has an average particlesize of about 5 microns or larger. In some instances, the particles havean average particle size of from about 15 to about 100 μm, or about15-200 microns, as measured by laser diffraction. In some instances, theparticles have an average particle size of from about 20 to about 50 μm,or about 50-150 microns, as measured by laser diffraction. In someinstances, the particles are spray dried. In some instances, the activeagent is spray dried onto the carrier, the thickening agent, or acombination thereof to form the particles. In some instances, thesolubility is measured at a pH ranging from about 6.8 to about 7.4. Insome instances, the particles comprise the carrier that is at leastpartially water insoluble at 37±0.5° C. In some instances, the waterinsolubility is measured at a pH ranging from about 6.8 to about 7.4. Insome instances, the particles further comprise the thickening agent, andwherein the carrier has lower water solubility than that of thethickening agent. In some instances, the particles comprise the carrierthat is at least partially adhesive to mucus. In some instances, theparticles comprise the carrier that comprises an oligosaccharide, apolysaccharide, or any combination thereof. In some instances, thecarrier comprises microcrystalline cellulose, ethyl cellulose, celluloseacetate, cellulose acetate butyrate, cellulose acetate propionate,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,starch, chitosan, β cyclodextrin, or any combination thereof. In someinstances, the particles comprise the carrier that has an averageparticle size of from about 10 to about 100 μm, as measured by laserdiffraction. In some instances, the carrier has an average particle sizeof about 20 or 23 μm, as measured by laser diffraction. In someinstances, the particles comprise the thickening agent that is at leastpartially water soluble at 37±0.5° C. In some instances, the watersolubility is measured at a pH ranging from about 6.8 to about 7.4. Insome instances, the particles further comprise the carrier, and whereinthe thickening agent has higher water solubility than that of thecarrier. In some instances, the particles comprise that the thickeningagent binds to the active agent. In some instances, the particlesfurther comprise the carrier, and wherein the thickening agent binds tothe active agent and the carrier. In some instances, the particlescomprise the thickening agent that comprises a polysaccharide. In someinstances, the thickening agent comprises hydroxypropyl methylcellulose(HPMC), hydroxypropyl cellulose, methyl cellulose,carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodiumalginate, xanthan gum, acacia, guar gum, locust bean gum, gumtragacanth, starch, carbopols, methylcellulose, polyvinylpyrrolidone, orany combination thereof. In some instances, the particles comprise thethickening agent and have an average particle size of from about 10 toabout 50 μm, as measured by laser diffraction. In some instances, theparticles have an average particle size of about 15 μm, or about 50-150microns, as measured by laser diffraction. In some instances, theparticles comprise the thickening agent, the sugar alcohol, and thecarrier and have an average particle size of from about 10 to about 50μm, or about 15-200 microns, as measured by laser diffraction. In someinstances, the particles have an average particle size of about 20 μm,or about 50-150 microns, as measured by laser diffraction. In someinstances, the pharmaceutical powder composition further comprises afluidizing agent. In some instances, the fluidizing agent comprises atribasic calcium phosphate. In some instances, the administration of thepharmaceutical powder composition improves the pharmacokinetic parameterof the active agent by at least about: 20%, 25%, 30%, 40%, 45%, 50%,60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, or 500%, whencompared to administration of the corresponding composition thatcomprises the active agent in the crystalline form. In some instances,the improved pharmacokinetic parameter comprises a greater relativebioavailability from 0 min to 15 min (rBA_(0-15min)), a greater relativebioavailability from 0 min to 30 min (rBA_(0-30min)), a greater relativebioavailability from 0 min to 60 min (rBA_(0-60min)), or any combinationthereof. In some instances, the improved pharmacokinetic parametercomprises an average rBA_(0-15min), and the improvement is at leastabout 100%, e.g., at least about: 115% or 150%. In some instances, theaverage rBA_(0-15min) is about 150% to 1500% in serum of the subject. Insome instances, the improved pharmacokinetic parameter comprises anaverage rBA_(0-30 min), and the improvement is at least about 80%, e.g.,at least about 115%. In some instances, the improvement is about 400%.In some instances, the improved pharmacokinetic parameter comprises anaverage rBA_(0-60min), and the improvement is at least 100%, e.g., atleast about 115%. In some instances, the improvement is about 200%. Insome instances, the improved pharmacokinetic parameter comprises ahigher maximum blood concentration (C_(max)). In some instances, theimproved pharmacokinetic parameter comprises a shorter time to reachmaximum blood concentration (T_(max)). In some instances, the improvedpharmacokinetic parameter comprises an increased area under the curve(AUC) for blood concentration-time profile. In some instances, thepharmaceutical powder composition further comprises an additional activeagent. In some instances, the additional active agent comprisescaffeine, which is amorphous, crystalline, at least 20% of amorphous byweight of the caffeine, or any combination thereof. In some instances,at least about: 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 98% by weight of the active agent is amorphous. Insome instances, the pharmaceutical powder composition retains at leastabout: 80%, 85%, 90%, or 95% by weight of the active agent in a closedcontainer after a period of at least about: 30, 60, 120, 180, 360, 720,or 1080 days. In some instances, the container is kept at about 20° C.to about 40° C. at a standard atmosphere pressure with a relativehumidity of about 50% to about 75%. In some instances, the container iskept at about 25° C. at a standard atmosphere pressure with a relativehumidity of about 50%. In some instances, the crystalline form comprisesa polymorph. In some instances, the method is used in the treatment of adisease or a condition in the human subject. In some instances, thedisease or condition is a headache, amyotrophic lateral sclerosis,Parkinson's disease, stress, anxiety, nausea, emesis, aggression, pain,neuropathic pain, sleeplessness, insomnia, restless leg syndrome,depression, or any combination thereof. In some instances, the diseaseor condition is a headache. In some instances, the headache is amigraine headache, a cluster headache, a hemicrania continua headache, achronic headache, a tension headache, a chronic tension headache, or anycombination thereof. In some instances, the headache is a migraineheadache. In some instances, the headache is a migraine headache withaura. In some instances, the headache is a migraine headache withoutaura. In some instances, the headache is moderate to severe. In someinstances, the headache is acute. In some instances, the pharmaceuticalpowder composition is administered for at least one day, two days, threedays, four days, five days, six days, one week, one month, or one year.In some instances, the administration of the pharmaceutical powdercomposition is 1, 2, 3, 4, 5, 6, 7, or 8 times daily. In some instances,the pharmaceutical powder composition is in a single unit dose. In someinstances, the pharmaceutical powder composition is a unit dose of fromabout 5 mg to about 50 mg, e.g., about 20 mg. In some instances, a unitdosage of the pharmaceutical powder composition contains about 0.1 mg toabout 10 mg of the active agent, e.g., about 4 mg. In some instances,the subject is a primate. In some instances, the subject is a human. Insome instances, the subject is a monkey.

In some cases, the present disclosure provides for a method of making anintranasal pharmaceutical powder composition, comprising spray drying,freeze-drying, or melt-extruding an active agent with at least onemember selected from the group consisting of a thickening agent, acarrier, a pH adjusting agent, a sugar alcohol, and any combinationthereof, to produce particles, wherein: at least about 20 percent byweight of the active agent in the particles is amorphous as determinedby X-ray diffraction; when the active agent has a crystalline form, asolubility of the active agent in a crystalline form in an aqueousliquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at atemperature of 37±0.5° C.; and the particles have an average particlesize of about 10 microns to about 300 microns, as measured by laserdiffraction. In some instances, the particles comprise the active agentand the thickening agent. In some instances, the particles comprise theactive agent and the carrier. In some instances, the particles comprisethe active agent, the carrier, and the thickening agent. In someinstances, the method further comprises blending the particles with anadditional amount of the carrier. In some instances, the method furthercomprises blending the particles with an additional carrier, additionalthickening agent, or any combination thereof. In some instances, theparticles comprise the active agent and are free from the thickeningagent, the carrier, or a combination thereof. In some instances, thesolubility is measured at a pH ranging from about 6.8 to about 7.4. Insome instances, the particles comprise the carrier that is at leastpartially water insoluble at 37±0.5° C. In some instances, the waterinsolubility is measured at a pH ranging from about 6.8 to about 7.4. Insome instances, the particles further comprise the thickening agent, andwherein the carrier has lower water solubility than that of thethickening agent. In some instances, the particles comprise the carrierthat is at least partially adhesive to mucus. In some instances, theparticles comprise the carrier that comprises an oligosaccharide, apolysaccharide, or any combination thereof. In some instances, thecarrier comprises microcrystalline cellulose, ethyl cellulose, celluloseacetate, cellulose acetate butyrate, cellulose acetate propionate,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,starch, chitosan, β cyclodextrin, or any combination thereof. In someinstances, the particles have an average particle size of from about 15to about 100 μm, as measured by laser diffraction. In some instances,the carrier has an average particle size of about 20 to about 50 μm, asmeasured by laser diffraction. In some instances, the particles comprisethe thickening agent that is at least partially water soluble 37±0.5° C.In some instances, the water solubility is measured at a pH ranging fromabout 6.8 to about 7.4. In some instances, the particles furthercomprise the carrier, and wherein the thickening agent has higher watersolubility than that of the carrier. In some instances, the particlescomprise the thickening agent that binds to the active agent. In someinstances, the particles further comprise the carrier, and wherein thethickening agent binds to the active agent and the carrier. In someinstances, the particles comprise thickening agent that comprises apolysaccharide. In some instances, the thickening agent compriseshydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose calcium, sodiumcarboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum,locust bean gum, gum tragacanth, starch, carbopols, methylcellulose,polyvinylpyrrolidone, or any combination thereof. In some instances, theparticles comprise the thickening agent and have an average particlesize of from about 10 to about 50 μm, or about 15-200 microns, asmeasured by laser diffraction. In some instances, the particles have anaverage particle size of about 15 μm, or about 50-150 microns, asmeasured by laser diffraction. In some instances, the particles comprisethe thickening agent, the sugar alcohol, and the carrier and have anaverage particle size of from about 10 to about 50 μm, as measured bylaser diffraction. In some instances, the particles an average particlesize of about 20 μm-100 μm, 20-50 μm, or about 50-150 microns, asmeasured by laser diffraction. In some instances, the active agent isspray dried, freeze-dried, or melt-extruded with the thickening agent.In some instances, the method further comprises using a fluid bedgranulation, e.g., after mixing all the components.

In some cases, the present disclosure provides for a use of anintranasal pharmaceutical powder composition disclosed herein in thetreatment of a disease or condition. In some instances, the disease orcondition is a headache, amyotrophic lateral sclerosis (ALS),Parkinson's disease, stress/anxiety, nausea, emesis, aggression, pain,neuropathic pain, sleeplessness, insomnia, restless leg syndrome, ordepression. In some instances, the disease or condition is a headache.In some instances, the headache is a migraine headache, a clusterheadache, a hemicrania continua headache, a chronic headache, a tensionheadache, a chronic tension headache, or any combination thereof. Insome instances, the headache is a migraine headache. In some instances,the headache is a migraine headache with aura. In some instances, theheadache is a migraine headache without aura. In some instances, theheadache is moderate to severe. In some instances, the headache isacute. In some instances, the pharmaceutical powder composition isadministered for at least one day, two days, three days, four days, fivedays, six days, one week, one month, or one year. In some instances, theintranasal pharmaceutical powder composition is administered 1, 2, 3, 4,5, 6, 7, or 8 times daily for the treatment. In some instances, theintranasal pharmaceutical powder composition is in a single unit dose,e.g., in an amount of about 5-50 mg or about 20 mg. In some instances, aunit dosage of the intranasal pharmaceutical powder composition containsabout 0.1 mg to about 10 mg of the active agent, e.g., about 4 mg. Insome instances, the subject is a primate. In some instances, the subjectis a human. In some instances, the subject is a monkey.

In some cases, the present disclosure provides for a device thatcontains a pharmaceutical powder composition disclosed herein. In someinstances, the device is for a single use.

In some cases, an active agent disclosed herein has an average particlesize larger than 5 μm.

In some cases, an active agent disclosed herein is suspended in methanolbefore spray drying or freeze-drying.

In some cases, an active agent is present in an amount of about 1-30%(e.g., 1-10%) by weight based on a weight of the particles or apharmaceutical powder composition, for example about: 20%, or 3%.

In some cases, particles comprise a thickening agent that is present inan amount of about 0.05-2% or about 0.05-10% by weight based on a weightof the particles or a pharmaceutical powder composition, for exampleabout 0.3% or about 5%. In some instances, particles comprise a sugaralcohol that is present in an amount of about 20-95% by weight based ona weight of the particles or a pharmaceutical powder composition, forexample about: 20%, 25%, 40%, 60%, 25%, 50%, 75%, or 90%. In someinstances, particles comprise the pH adjusting agent that is present inan amount of about 1-40% by weight based on a weight of the particles ora pharmaceutical powder composition, for example about: 2.5%, 5%, 15%,or 25%.

In some cases, a particle or composition disclosed herein comprises a pHadjusting agent. In some instances, the pH adjusting agent is selectedfrom the group consisting of ascorbic acid, sodium ascorbate, tartaricacid, sodium tartrate, potassium tartrate, calcium tartrate, lithiumtartrate, citric acid, sodium citrate, potassium citrate, calciumcitrate, lithium citrate, phosphoric acid, sodium dihydrogenphosphate,sodium monohydrogenphosphate, lithium phosphate, potassium phosphate,calcium phosphate, sodium carbonate, sodium hydrogencarbonate, lacticacid, sodium lactate, potassium lactate, calcium lactate, acetic acid,sodium acetate, potassium acetate, calcium acetate, propionic acid,sulphuric acid, sodium sulphate, potassium sulphate, boric acid, sodiumborate, maleic acid, lithium maleate, sodium maleate, potassium maleate,calcium maleate, succinic acid, lithium succinate, sodium succinate,potassium succinate, calcium succinate, fumaric acid, glutamic acid,formic acid, malic acid, hydrochloric acid, nitric acid, sodiumhydroxide, potassium hydroxide, triethanolamine, diisopropanolamine,ammonia solution, monoethanole amine, diethanoleamine, triethanoleaminemeglumine, sodium citrate, sodium bicarbonate, potassium bicarbonate,and any combination thereof.

In some cases, a particle or composition disclosed herein comprises asugar alcohol. In some instances, the sugar alcohol is selected from thegroup consisting of mannitol, glycerol, galactitol, fucitol, inositol,volemitol, maltotriitol, maltoetetraitol, polyglycitol, erythritol,threitol, ribitol, arabitol, xylitol, allitol, dulcitol, glucitol,sorbitol, altritol, iditol, maltitol, lactitol, isomalt, and anycombination thereof.

In some cases, a pharmacokinetic parameter disclosed herein isdetermined with an analysis of a blood or plasma sample collected at oneor more time points of about 2, 5, 10, 15, 20, 30, 45, 60, 120, or 180minutes after intranasal administration. In some instances, the analysiscomprises a measurement of a plasma concentration of DHE,8′-hydroxy-DHE, or a combination thereof in the blood or plasma sample.In some instances, the analysis is conducted with liquid chromatography(LC), mass spectrometry (MS), or a combination thereof. In someinstances, the analysis is conducted with a LC/MS/MS method.

In some instances, the pharmaceutical powder composition disclosedherein comprises dihydroergotamine or a pharmaceutically acceptable saltthereof, mannitol, and microcrystalline cellulose. In some instances,the pharmaceutical powder composition further comprises HPMC. In somecases, the present disclosure provides a pharmaceutical powdercomposition that comprises: 1) about 1-8 mg such as 4 mg ofdihydroergotamine or a pharmaceutically acceptable salt thereof 2) about5-15 mg such as 5 mg of mannitol; and 3) about 5-15 mg such as 11 mg ofmicrocrystalline cellulose. In some instances, the pharmaceutical powdercomposition has an average particle size diameter of about 20 to about100 microns. In some instances, the pharmaceutical powder composition isfor intransal administration. In some cases, the present disclosuresprovides a pharmaceutical powder composition that comprises: 1)dihydroergotamine or a pharmaceutically acceptable salt thereof that ispresent in about 20% of a total weight of the pharmaceutical powdercomposition; optionally 2) HPMC that is present in about 5% of the totalweight of the pharmaceutical powder composition; 3) mannitol that ispresent in about 25% of the total weight of the pharmaceutical powdercomposition; and 4) microcrystalline cellulose that is present in about50% or 55% of the total weight of the pharmaceutical powder composition,and wherein the pharmaceutical powder composition have an averageparticle size diameter of about 50 to about 150 microns. In someinstances, the pharmaceutical powder composition is for intransaladministration. In some cases, the present disclosures provides apharmaceutical powder composition that comprises: 1) about 4 mg ofdihydroergotamine or a pharmaceutically acceptable salt thereof; 2)about 1 mg of HPMC; 3) about 5 mg of mannitol; and 4) about 10 mg ofmicrocrystalline cellulose, and wherein the pharmaceutical powdercomposition have an average particle size diameter of about 50 to about150 microns. In some instances, the pharmaceutical powder composition isfor intransal administration.

In some cases, the present disclosure provides particles that comprisean active agent, a carrier, a sugar alcohol, or any combination thereof.In some instances, the particles further comprise a thickening agent. Insome instances, the particles are substantially uniform. In someinstances, at least about: 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, or 95% by weight of the particles are agglomerated, aggregated, ora combination thereof. In some instances, about: 10%-15%, 20%-30%,40%-50%, 60%-70%, 80%-90%, 95%-99%, 10%-25%, 20%-40%, 40%-60%, 60%-80%,80%-95%, 10%-30%, 10%-40%, 10%-50%, 30%-70%, 50%-90%, or 70%-99% byweight of the particles are agglomerated, aggregated, or a combinationthereof. In some instances, the particles are substantiallyagglomerated, aggregated, or a combination thereof. In some instances,the active agent is aggregated or agglomerated, with the carrier, thesugar alcohol, or a combination thereof. In some instances, the sugaralcohol is aggregated or agglomerated, with the carrier. In someinstances, the active agent is DHE or a pharmaceutically acceptable saltthereof. In some instances, the thickening agent is HPMC. In someinstances, the carrier is microcrystalline cellulose. In some instances,the sugar alcohol is mannitol. In some instances, an average diameter ofthe particles is about 15 microns to about 200 microns, for exampleabout 50 microns to about 150 microns, or about 20 microns to about 50microns.

In some instances, the intranasal pharmaceutical powder compositiondisclosed herein comprises particles that have one or more followingfeatures: at least some of the particles disclosed herein substantiallycontain a single ingredient selected from the group consisting of anactive agent, a thickening agent, a carrier, a pH adjusting agent, and asugar alcohol; or at least some of the particles contain a singleingredient selected from the group consisting of the active agent, thethickening agent, the carrier, the pH adjusting agent, and the sugaralcohol; or at least some of the particles contain at least twoingredients selected from the group consisting of the active agent, thethickening agent, the carrier, the pH adjusting agent, and the sugaralcohol; or the intranasal pharmaceutical powder composition furthercomprises particles that comprise the active agent and are free from thethickening agent, the carrier, or a combination thereof; or at leastsome of the particles are aggregates; or at least some of the particlesare agglomerates; or any combination thereof. In some cases, the presentdisclosure provides agglomerated particles that comprise an activeagent, a thickening agent, a carrier, and a sugar alcohol. In someinstances, the active agent is DHE or a pharmaceutically acceptable saltthereof. In some instances, the thickening agent is HPMC. In someinstances, the carrier is microcrystalline cellulose. In some instances,the sugar alcohol is mannitol. In some instances, an average diameter ofthe agglomerated particles is about 15 microns to about 200 microns. Insome instances, the average diameter of the agglomerated particles isabout 50 microns to about 150 microns.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different instances, and itsseveral details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative instances,in which the principles of the invention are utilized, and theaccompanying drawings (also “figure” and “FIG.” herein), of which:

FIGS. 1A to 1F are a group of line graphs comparing DHE pharmacokineticprofiles in monkeys from testing various DHE formulations, for 0-180min.

FIGS. 2A and 2B are a group of bar graphs comparing AUC profiles ofvarious DHE formulations, tested in monkeys.

FIGS. 3A, 3B, and 3C are a group of X-ray diffraction spectra overlaycomparing various DHE formulations.

FIG. 4 is a group of scanning electron microscope (SEM) scans of variousDHE formulations.

FIG. 5 is a graph showing plasma indomethacin concentration-timeprofiles in monkeys.

FIG. 6 is a graph showing X-ray diffraction spectra of freeze-driedindomethacin and non-treated indomethacin.

FIG. 7 is a graph showing plasma testosterone concentration-timeprofiles in monkeys.

FIG. 8 is a graph comparing X-ray diffraction spectra of freeze-driedtestosterone and non-treated testosterone.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of the ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the compositions or unit dosesherein, some methods and materials are now described. Unless mentionedotherwise, the techniques employed or contemplated herein are standardmethodologies. The materials, methods and examples are illustrative onlyand not limiting.

The details of one or more inventive instances are set forth in theaccompanying drawings, the claims, and the description herein. Otherfeatures, objects, and advantages of the inventive instances disclosedand contemplated herein can be combined with any other instance unlessexplicitly excluded.

Unless otherwise indicated, open terms for example “contain,”“containing,” “include,” “including,” and the like mean comprising.

The singular forms “a”, “an”, and “the” are used herein to includeplural references unless the context clearly dictates otherwise.Accordingly, unless the contrary is indicated, the numerical parametersset forth in this application are approximations that may vary dependingupon the desired properties sought to be obtained by the presentinvention.

Unless otherwise indicated, some instances herein contemplate numericalranges. When a numerical range is provided, unless otherwise indicated,the range includes the range endpoints. Unless otherwise indicated,numerical ranges include all values and subranges therein as ifexplicitly written out. Unless otherwise indicated, any numerical rangesand/or values herein can be at 80-125% of the numerical ranges and/orvalues.

A standard atmosphere (symbol: atm) is a unit of pressure defined as101325 Pa (1.01325 bar), equivalent to 760 mmHg (torr), 29.92 inHg, or14.696 psi.

In some instances, improvement is calculated as the following:

Improvement=(|I−C|/C)×D _(I) /D _(c)×100%

I=Improved value from a present composition

C=Control value from a comparator or conventional composition

D_(I)=Dose of the present composition

D_(c)=Dose of the comparator or conventional composition

Unless otherwise indicated, relative bioavailability (rBA) is equal to[(AUC of preparation with amorphous API/Dose of preparation withamorphous)/(AUC of preparation with 100% crystal/Dose of preparation of100% crystal)×100%].

In some instances, a buffering agent is selected from the groupconsisting of sodium phosphate, sodium hydrogenphosphate, anhydroussodium dihydrogenphosphate, crystalline sodium dihydrogenphosphate,disodium hydrogenphosphate, potassium phosphate, potassiumdihydrogenphosphate, dipotassium phosphate, boric acid, borax, sodiumacetate, citric acid, citric anhydride, sodium citrate, sodiumglutamate, creatinine, and phosphate buffered saline.

Unless otherwise indicated, the term “thickening agent” refers to anexcipient that increases a particle size of an active agent and/orviscosity of a composition. In some instances, a thickening agentdisclosed herein binds to an active agent and/or a carrier via anon-covalent interaction, e.g., hydrogen bonding or van der Waals force.

Unless otherwise indicated, “average particle size” can refer to aparticle size distribution of a powder in its non-aggregated state. Insome instances, an average particle size refers to a mean particle size,for example calculated as a sum of size measurements of all measurableparticles divided by a total number of particles measured. In someinstances, an average particle size refers to a median particle size,for example indicating that about 50% of all measurable particlesmeasured have a particle size less than the defined median particle sizevalue, and that about 50% of all measurable particles measured have aparticle size greater than the defined median particle size value. Insome instances, an average particle size refers to a mode particle size,for example indicating the most frequently-occurring particle sizevalue. In some instances, for spherical particles, an average particlesize is a measurement of a particle's diameter. In some instances, fornon-spherical particles, an average particle size is a measurement oflongest or shortest diameters, perimeter, projected area, or by anequivalent spherical diameter. Primary particle diameter can bedetermined using a laser-diffraction particle size analyzer. In someinstances, the particle size analyzer can be Mastersizer 2000manufactured by Malvern Instruments Limited.

Pharmacokinetic data disclosed herein (e.g., C_(max), T_(max),AUC_(0-t), AUC_(0-180 minutes), AUC_(0-inf), T_(1/2)) can be measuredfrom a primate, preferably a monkey, and preferably a Cynomolgus monkey,after a powder composition disclosed herein is administered.Alternatively, the pharmacokinetic data disclosed herein (e.g., C_(max),T_(max), AUC_(0-t), AUC_(0-180 minutes), AUC_(0-inf), T_(1/2)) can bemeasured from a human subject after a powder composition disclosedherein is administered. In some instances, an active agent such asdihydroergotamine, or a complex, chelate, salt, hydrate, polymorph, orion pair thereof is administered at a rate such that a mean peak plasmaconcentration (C_(max)) of 8-hydroxy dihydroergotamine is higher than10,000 pg/ml, and a mean time to C_(max) (T_(max)) of 8-hydroxydihydroergotamine is longer than 45 minutes.

Presented herein are compositions, comprising an active agent. In someinstances, the active agent is in a free base form. In some instances,the active agent is in a pharmaceutically acceptable salt form. In someinstances, the term “substantially” can mean 80-100% of a referredsubject matter. In some instances, agglomerate can mean a looseaccumulation of separate particles bonded by weak physical forces. Insome instances, aggregate can mean a dense cluster of separate particlesbonded by strong chemical or sinter forces.

Intranasal administration, as used herein in the context of the powdercompositions presented herein, unless otherwise noted, refers toadministration whereby at least 95±5% of the powder composition isadministered to the nasal cavity as measured by multiple path particledosimetry (MPPD) model analysis, a computational model used to estimatehuman airway particle dosimetry (see, e.g., Anjilvel, S. and Asgharian,B. (1995) Fundam. Appl. Toxicol. 28, 41-50; and National Institute forPublic Health and the Environment (RIVM) (2002) Multiple Path ParticleDosimetry Model (MPPD v 1.0): A Model for Human and Rat Airway ParticleDosimetry. Bilthoven, The Netherlands. RIVA Report 650010030), or via anAndersen Cascade Impactor.

In some instances, not less than 90% of the particles in the powdercompositions presented herein have a diameter less than 150 μm, and notmore than 5% of the particles in the powder compositions have a diameterless than 10 μm. In some instances, the overall average particle size ofthe particles in the powder compositions presented herein is about 15 toabout 30 μm, about 18 to about 25 μm, about 18 to about 20 μm, or about20 μm.

In some instances, presented herein is a method of treating a disease orcondition, e.g., pain, headache (e.g., migraine), hormone disorder,comprising intranasally administering to a human, a compositioncomprising an active agent, or a pharmaceutically acceptable saltthereof, microcrystalline cellulose, and tribasic calcium phosphate,wherein the composition is not a liquid solution or a liquid spraycomposition. Unless noted, such compositions are referred to herein aspowder compositions. In some instances, a method disclosed hereincomprises intranasally administering powder compositions comprising anactive agent, microcrystalline cellulose with an average particlediameter size of about 100 μm or less, and tribasic calcium phosphate.Throughout, unless otherwise noted, “about” means within ±10% of avalue. For example, if it is stated that a component makes up “about70%” of a mixture, it is implied that the component makes up within arange of 63% and 77% of the mixture. In addition, in instances wherein“about” is used, it is to be understood that instances involving theexact value associated with “about” are also contemplated. For example,when an instance recites “about 0.5 milligram (mg) of an active agent,”an instance reciting “0.5 mg of an active agent” is also contemplatedand is described herein.

In some cases, provided herein are methods of treating a disease orcondition, e.g., pain, headache (e.g., migraine), hormone disorder,comprising intranasally administering powder compositions comprising anactive agent, a microcrystalline cellulose portion with an averageparticle size diameter of about 50-55 μm, e.g., 50 μm, comprising about10% of the total weight of the powder composition, a microcrystallinecellulose portion with an average particle size of about 20 μmcomprising about 3 to about 90%, e.g., 8 to about 90%, of the totalweight of the powder composition and, optionally, a fluidizing agent. Insome instances, the powder compositions utilized as part of the methodsfurther comprise an active agent disclosed herein, e.g., caffeine, forexample, anhydrous caffeine. Throughout, unless otherwise noted, percent(%) weight, in the context of the powder compositions presented herein,refers to weight per weight percent (%) (W/W %).

In some cases, presented herein are powder compositions that can beutilized in conjunction with the methods of treating a disease orcondition, e.g., pain, headache (e.g., migraine), hormone disorder,wherein the powder compositions comprise an active agent or apharmaceutically acceptable salt thereof. In some instances, providedherein are powder compositions comprising: a) an active agent b)microcrystalline cellulose, e.g., a microcrystalline cellulose with anaverage particle diameter size of about 100 μm or less; and c) tribasiccalcium phosphate. In some instances, provided herein are powdercompositions comprising an active agent, a microcrystalline celluloseportion with an average particle size diameter of about 50-55 μm, e.g.,50 μm, comprising about 10% of the total weight of the powdercomposition, a microcrystalline cellulose portion with an averageparticle size of about 20 μm comprising about 3% to about 90%, e.g.,about 8 to about 90%, of the total weight of the powder composition and,optionally, a fluidizing agent. In some instances, the powdercompositions further comprise an active agent disclosed herein, e.g.caffeine, for example, anhydrous caffeine. In some instances, greaterthan or equal to about 90% of the particles in the powder compositionhave a diameter less than 150 μm. In some instances, the overall averageparticle size of the composition is about 15 to about 30 μm, about 18 toabout 25 μm, about 18 to about 20 μm, or about 20 μm. In some instances,less than or equal to about 5% of the particles in the powdercomposition have a diameter less than 10 μm. In some instances, greaterthan or equal to about 90% of the particles in the powder compositionhave a diameter less than 150 μm; and the overall average particle sizeof the composition is about 15 to about 30 μm, about 18 to about 25 μm,about 18 to about 20 μm, or about 20 μm; and less than or equal to about5% of the particles in the powder composition have a diameter less than10 μm.

In some cases, a powder composition disclosed herein comprises an activeagent, microcrystalline cellulose, and tribasic calcium phosphate. Insome instances, the microcrystalline cellulose comprises a firstmicrocrystalline cellulose (e.g., average particle size of about 20 μm)and a second microcrystalline cellulose (e.g., average particle size ofabout 50 In).

In some cases, a powder composition disclosed herein has an angle ofrepose about 53° or less, for example, about 53°, 52°, 51°, 50°, 48°,46°, 44°, 42°, 40°, 38°, 36°, 34°, 32°, 30°, 28°, 26°, 24°, 22°, 20° orless.

In some cases, presented herein are methods and compositions used fortreating a disease or a condition, e.g., headache, pain, or hormonedisorder. For example, the methods and compositions are used fortreating migraine. In some instances, the methods of treating migraineare methods for the acute treatment of migraine headaches with orwithout aura. In some instances, at least a portion of the powdercomposition is administered to a single nostril of the human. In someinstances, at least a portion of the powder composition is administeredto each nostril of the human. For example, in some instances of themethod, about half of the composition is administered to one nostril andabout half of the composition is administered to the other nostril ofthe human.

In some cases, the present disclosure provides for a device thatcontains a pharmaceutical powder composition disclosed herein. In someinstances, the device is for a single use.

Active Agents and Compositions

In some cases, an active agent disclosed herein is anon-peptide/non-protein drug. In some instances, the active agent isselected from the group consisting of ergot alkaloid,5-hydroxytryptaminel (5-HT1) receptor agonist, CGRP antagonist, NK-1receptor antagonist, antihistamine, antiemetic agent, decongestant,opioid receptor agonist, antibiotic, antifungal agent, sulfa drug,antituberculosis drug, antimicrobial agent, antiviral agent, hypnoticsedative, antiepileptic agent, narcotic analgesic, nonnarcoticanalgesic, sedative drug, psychotherapeutic agent, muscle relaxant,antiallergic agent, anti-rheumatic drug, cardiotonic drug,antiarrhythmic agent, antihypertensive agent, diuretic agent, coronaryvasodilator, antidementia drug, brain activator, brain circulationameliorating agent, antiparkinsonian agent, antihyperlipidemic drug,antiulcer drug, obesity drug, diabetic drug, hemostatic drug,antithrombotic agent, migraine drug, antitussive drug, expectorant,respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidalantiinflammatory agent, antipodagric, therapeutic agent for urinarydisease, drug for improving sexual function, agent for the uterus,steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavymetal toxification, quit smoking agent, antianaphylactic agent,antitumor agent, immunostimulator, immunosuppressive drug, and anycombination thereof. In some instances, the active agent is selectedfrom the group consisting of didanosine, zidovudine, lamivudine,acyatazanavir, nelfenavir, sanilvudine, emtricitabine,polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir,peramivir, laninamivir, favipiravir, amantadine, amphotericin B,miconazole, fluconazole, itraconazole, ketoconazole, ketamine,pentobarbital sodium, thiopental, amopentobarbital, hexobarbital,lidocaine, triazolam, zopiclone, zolpidem, eszopiclone, etizolam,clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam,flunitrazepam, diazepam, chlordiazepoxide HCl, alprazolam, lorazepam,ethyl loflazepate, bromazepam, rilmazafone, chloral hydrate,carbamazepine, clonazepam, zonisamide, sodium valproate, phenytoin,phenobarbital, primidone, gabapentin, opium, morphine, ethylmorphine,oxycodone, hydrocodone, codeine, dihydrocodeine, fentanyl, remifentanil,droperidol, levorphanol, methadone, meperidine, pethidine,buprenorphine, butorphanol, tramadol, tapentadol, nalfurafine,pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine,levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine,dihydroergotamine, sumatriptan, eletriptan, zolmitriptan, rizatriptan,naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan,olcegepant, telcagepant, donepezil, suxamethonium, pancuronium,sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine,homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine,thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide,nitroglycerin, quinidine, disopyramide, dopamine, dobutamine,epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine,doxapram, naloxone, flumazenil, tipepidine, dextromethorphan, ambroxol,bromhexine, salbutamol, terbutaline, procaterol, theophylline,ephedrine, sodium cromoglycate, ketotifen, oxatomide, tranilast,granisetron, azasetron, ramosetron, tropisetron, indisetron,palonosetron, cisapride, domperidone, metoclopramide, trimebutine,loperamide, mefenamic acid, indomethacin, sulindac, ibuprofen,ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenicacid, tiaramide, carbazochrome sulfonic acid, tranexamic acid,pralidoxime iodide methyl, progesterone, testosterone,dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine,leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone,risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir,famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine,idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin,carmustin, beraprost sodium, and any combination thereof.

In some instances, the active agent is a small molecule drug, e.g.,having a molecular weight of less than about 1000 grams/mole (g/mol),about 750 g/mol, or about 500 g/mol. In some instances, the active agentis an anti-migraine drug. In some instances, the active agent is anergot alkaloid. In some instances, the active agent is dihydroergotamine(DHE) or a pharmaceutically acceptable salt thereof, e.g., DHE mesylate.In some instances, the active agent is indomethacin, midazolam, orphenobarbital. In some instances, the active agent is indomethacin or apharmaceutically acceptable salt thereof. In some instances, the activeagent is testosterone or a pharmaceutically acceptable salt thereof.

In some cases, an active agent disclosed herein is a peptide or apeptide-related compound, wherein the peptide or peptide-relatedcompound has a molecular weight of about 10,000 Daltons (Da) or less,about 20,000 (Da) or less, about 30,000 (Da) or less, about 40,000 (Da)or less, or about 50,000 Daltons or less. In some instances, the activeagent is selected from the group consisting of insulin, human growthhormone, calcitonin, glucagon, parathyroid hormone, parathyroid hormone(1-34), glucagon-like peptide-1, interferon, interleukin,erythropoietin, luteinizing hormone-releasing hormone, somatostatin,vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growthhormone-releasing hormone, granulocyte colony formation-stimulatingfactor, parathyroid hormone, thyroid-stimulating hormone-releasinghormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitorypolypeptide (GIP), C-peptide, cyclosporine, FK-506, octreotide,carperitide, pramlintide, lanreotide, eptifibatide, albiglutide,pasireotide, teriparatide, exenatide, liraglutide, emfuvirtide,ziconotide, ecallantide, mifamurtide, nesiritide, peglinesatide,afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide,cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide,a peptide analog thereof, and any combination thereof.

Methods and compositions presented herein can utilize an active agent ina freebase, salt, hydrate, polymorph, isomer, diastereomer, prodrug,metabolite, ion pair complex, or chelate form. An active agent can beformed using a pharmaceutically acceptable non-toxic acid or base,including an inorganic acid or base, or an organic acid or base. In someinstances, an active agent that can be utilized in connection with themethods and compositions presented herein is a pharmaceuticallyacceptable salt derived from acids including, but not limited to, thefollowing: acetic, alginic, anthranilic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, or p-toluenesulfonic acid. In some instances,the active agent is a salt of methanesulfonic acid. An alternativenomenclature of the methanesulfonic acid salt of DHE is DHE mesylate.For further description of pharmaceutically acceptable salts that can beused in the methods described herein see, for example, S. M. Barge etal., “Pharmaceutical Salts,” 1977, J. Pharm. Sci. 66:1-19, which isincorporated herein by reference in its entirety.

In some cases, an average particle size of an active agent or acomposition disclosed herein can be less than about 100 micrometer (μm),for example, about: 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm, 60μm, 55 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10μm, 5 μm or less. In some instances, an average particle size of anactive agent or a composition disclosed herein can be larger than 10 μm,for example, more than about: 250 μm, 200 μm, 190 μm, 180 μm, 170 μm,160 μm, 150 μm, 140 μm, 130 μm, 120 μm, 110 μm, 100 μm, 95 μm, 90 μm, 85μm, 80 μm, 75 μm, 70 μm, 65 μm, 60 μm, 55 μm, 50 μm, 45 μm, 40 μm, 35μm, 30 μm, 25 μm, 20 μm, or 15 μm. The particle size of an active agentor a powder composition can be about: 20-100 microns, 25-150 microns,25-175 microns, 25-200 microns, 25-250 microns, 25-300 microns, 50-150microns, 50-175 microns, 50-200 microns, 50-250 microns, 50-300 microns,10-100 μm, for example, about: 15-90 μm, 15-80 μm, 15-70 μm, 15-60 μm,15-50 μm, 15-40 μm, 15-30 μm, 15-20 μm, 15-20 μm, 10-90 μm, 10-80 μm,10-70 μm, 10-60 μm, 10-50 μm, 10-40 μm, 10-30 μm, 10-20 μm, 20-90 μm,20-80 μm, 20-70 μm, 20-60 μm, 20-50 μm, 20-40 μm, 20-30 μm, 30-90 μm,30-80 μm, 30-70 μm, 30-60 μm, 30-50 μm, 30-40 μm, 40-90 μm, 40-80 μm,40-70 μm, 40-60 μm, 40-50 μm, 50-90 μm, 50-80 μm, 50-70 μm, 50-60 μm,60-90 μm, 60-80 μm, 60-70 μm, 70-90 μm, 70-80 μm, or 80-90 μm. Theaverage particle size of the active agent or the composition can beabout: 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm, 8.5 μm,9.0 μm, 9.5 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm,18 μm, 19 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, or 100 μm. In someinstances, not less than 90% of the powder compositions presented hereinhave a particle diameter less than 150 μm, and not more than 5% of theparticles have a diameter less than 5 μm. In some instances, the overallaverage particle size of the powder compositions presented herein areabout 15 μm to about 30 μm, about 18 μm to about 25 μm, about 18 μm toabout 20 μm, or about 20 μm.

In some cases, a total weight of a powder composition comprises about0.4% to about 46%, or about 0.4% to about 23% or about 0.4% to about 9%,or about 2% to about 9%, or about 4% to about 9% of an active agent. Insome instances, the total weight of the powder composition comprisesabout 0.3% to about 37%, or about 0.3% to about 18% or about 0.3% toabout 7%, or about 2% to about 7%, or about 3% to about 9% of an activeagent or a pharmaceutically acceptable salt thereof.

In some cases, a composition disclosed herein further comprises anadditional active agent, for example: an adenosine receptor antagonist,a phosphodiesterase inhibitor, an acetylcholinesterase inhibitor, avasodilator, xanthine, caffeine, paraxanthine, theobromine, andtheophylline. For example, the methods and compositions further comprisecaffeine. The additional active agent (e.g., caffeine) can be at leastabout 1% of the total weight of the powder composition, for exampleabout: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60% or more of the total weight of the powdercomposition. The additional active agent (e.g., caffeine) can be about1% to 60% of the total weight of the powder composition, for example,about: 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-20%, 1%-10%, 1%-5%, 10%-60%,10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-60%, 20%-50%, 20%-40%, 20%-30%,30%-60%, 30%-50%, 30%-40%, 40%-60%, 40%-50%, or 50%-60% of the totalweight of the powder composition. In some instances, the powdercomposition comprises about 5% to 10% of an additional active agent(e.g., caffeine). In some instances, the caffeine is anhydrous caffeine.In some instances, the powder composition comprises about 10% to 15% ofan additional active agent (e.g., caffeine).

In some cases, the present disclosure provides for an intranasalpharmaceutical powder composition comprising particles that comprise anactive agent and at least one member selected from the group consistingof a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol,and any combination thereof, wherein: at least about 10%, about 20%,about 30%, about 40%, or about 50% by weight of the active agent in theparticles is amorphous as determined by X-ray diffraction; when theactive agent has a crystalline form, a solubility of the active agent ina crystalline form in an aqueous liquid ranges from about 0.1 μg/mL toabout 1 milligram/milliliter (mg/mL) in water at a temperature of37±0.5° C.; the particles have an average particle size of about 10microns to about 300 microns, as measured by laser diffraction; and whenthe intranasal pharmaceutical powder composition is administered, apharmacokinetic parameter of the active agent improves by at least about15%, compared to a corresponding composition that comprises the activeagent in a crystalline form when administered. In some instances, thepharmaceutical powder composition further comprises particles thatcomprise the active agent and are free from the thickening agent, thecarrier, the pH adjuster, the sugar alcohol, or a combination thereof.In some instances, the active agent is a non-peptide/non-protein drug.In some instances, the particles have an average particle size of fromabout 15 to about 100 μm, as measured by laser diffraction. In someinstances, the particles have an average particle size of from about 20to about 50 μm, as measured by laser diffraction. In some instances, theparticles are spray dried. In some instances, the active agent is spraydried onto the carrier, the thickening agent, the pH adjuster, the sugaralcohol or a combination thereof to form the particles. In someinstances, the solubility is measured at a pH of about 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.8,7.9, 7.10, for example, ranging from about 6.8 to about 7.4. In someinstances, the particles comprise the carrier that is at least partiallywater insoluble at 37±0.5° C. In some instances, the water insolubilityis measured at a pH ranging from about 6.8 to about 7.4. In someinstances, the particles further comprise the thickening agent, andwherein the carrier has lower water solubility than that of thethickening agent. In some instances, the particles comprise the carrierthat is at least partially adhesive to mucus. In some instances, theparticles comprise the carrier that comprises an oligosaccharide, apolysaccharide, or any combination thereof. In some instances, thecarrier comprises microcrystalline cellulose, ethyl cellulose, celluloseacetate, cellulose acetate butyrate, cellulose acetate propionate,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,starch, chitosan, β cyclodextrin, or any combination thereof. In someinstances, the particles comprise the carrier that has an averageparticle size of from about 10 to about 100 μm, as measured by laserdiffraction. In some instances, the carrier has an average particle sizeof about 20 μm, as measured by laser diffraction. In some instances, theparticles comprise the thickening agent that is at least partially watersoluble at 37±0.5° C. In some instances, the water solubility ismeasured at a pH ranging from about 6.8 to about 7.4. In some instances,the particles further comprise the carrier, and wherein the thickeningagent has higher water solubility than that of the carrier. In someinstances, the particles comprise that the thickening agent binds to theactive agent. In some instances, the particles further comprise thecarrier, and wherein the thickening agent binds to the active agent andthe carrier. In some instances, the particles comprise the thickeningagent that comprises a polysaccharide. In some instances, the thickeningagent comprises hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, methyl cellulose, carboxymethylcellulose calcium, sodiumcarboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum,locust bean gum, gum tragacanth, starch, carbopols, methylcellulose,polyvinylpyrrolidone, or any combination thereof. In some instances, theparticles comprise the thickening agent and have an average particlesize of from about 10 to about 50 μm, or about 15-200 microns, asmeasured by laser diffraction. In some instances, the particles have anaverage particle size of about 15 μm, or about 50-150 microns, asmeasured by laser diffraction. In some instances, the particles comprisethe thickening agent and the carrier and have an average particle sizeof from about 10 to about 50 μm, as measured by laser diffraction. Insome instances, the particles have an average particle size of about 20or about 23 μm, as measured by laser diffraction. In some instances, thepharmaceutical powder composition further comprises a fluidizing agent.In some instances, the fluidizing agent comprises a tribasic calciumphosphate. In some instances, the administration of the pharmaceuticalpowder composition improves the pharmacokinetic parameter of the activeagent by at least about: 20%, 25%, 30%, 40%, 45%, 50%, 60%, 70%, 80%,90%, 100%, 150%, 200%, 250%, 300%, 400%, or 500%, when compared toadministration of the corresponding composition that comprises theactive agent in the crystalline form. In some instances, the improvedpharmacokinetic parameter comprises a greater relative bioavailabilityfrom 0 min to 15 min (rBA_(0-15min)), a greater relative bioavailabilityfrom 0 min to 30 min (rBA_(0-30min)), a greater relative bioavailabilityfrom 0 min to 60 min (rBA_(0-60min)), or any combination thereof. Insome instances, the improved pharmacokinetic parameter comprises anaverage rBA_(0-15min), and the improvement is at least about 100%, e.g.,at least about: 115% or 150%. In some instances, the averagerBA_(0-15min) is about 150% to 1500% in serum of the subject. In someinstances, the improved pharmacokinetic parameter comprises an averagerBA_(0-30min), and the improvement is at least about 80%, e.g., at leastabout 115%. In some instances, the improvement is about 400%. In someinstances, the improved pharmacokinetic parameter comprises an averagerBA_(0-60min), and the improvement is at least 100%, e.g., at leastabout 115%. In some instances, the improvement is about 200%. In someinstances, the improved pharmacokinetic parameter comprises a highermaximum blood concentration (C_(max)). In some instances, the improvedpharmacokinetic parameter comprises a shorter time to reach maximumblood concentration (Tmax). In some instances, the improvedpharmacokinetic parameter comprises an increased area under the curve(AUC) for blood concentration-time profile. In some instances, thepharmaceutical powder composition further comprises an additional activeagent. In some instances, the additional active agent comprisescaffeine, which is amorphous, crystalline, at least 20% of amorphous byweight of the caffeine, or any combination thereof. In some instances,at least about: 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 98% by weight of the active agent is amorphous. Insome instances, the pharmaceutical powder composition retains at leastabout: 80%, 85%, 90%, or 95% by weight of the active agent in a closedcontainer after a period of at least about: 30, 60, 120, 180, 360, 720,or 1080 days. In some instances, the container is kept at about 15° C.,about 20° C., about 30° C., about 40° C., about 50° C., about 60° C., orabout 70° C., for example about 20° C. to about 40° C. at a standardatmosphere pressure with a relative humidity of about 50% to about 75%.For example, the relative humidity may be about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,or about 85%. In some instances, the container is kept at about 25° C.at a standard atmosphere pressure with a relative humidity of about 50%.In some instances, the crystalline form comprises a polymorph.

In some cases, an active agent disclosed herein has an average particlesize (e.g., diameter) of 5 μm or larger than 5 μm.

In some cases, an active agent disclosed herein is suspended in methanolbefore spray drying.

In some cases, an active agent is present in an amount of about: 2-4%,1-5%, 1-10%, 1-15%, 1-20%, 1-25%, 1-30%, 1-40%, 10-50%, 10-40%, 10-30%,or 15-25%, by weight based on a weight of the particles or apharmaceutical powder composition, for example about: 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, or50%.

In some cases, particle size for each active agent, excipient and powderpreparation are determined under a dry powder dispersion condition by alaser diffraction system (Mastersizer 2000, Malvern Instruments Ltd.).

Pharmacokinetics

Pharmacokinetic data disclosed herein (e.g., C_(max), T_(max),AUC_(0-t), AUC_(0-180 minutes), AUC_(0-inf), T_(1/2)) can be measuredfrom a primate, preferably a monkey, and preferably a Cynomolgus monkey,after a powder composition disclosed herein is administered.Alternatively, the pharmacokinetic data disclosed herein (e.g., C_(max),T_(max), AUC_(0-t), AUC_(0-180 minutes), AUC_(0-inf), T_(1/2)) can bemeasured from a human subject after a powder composition disclosedherein is administered.

Presented herein are powder compositions comprising an active agent. Inaddition to such compositions, also presented herein are methodscomprising intranasally administering powder compositions containingdihydroergotamine, or a pharmaceutically acceptable salt thereof. Insome cases, the composition may not be a liquid solution or a liquidspray composition.

Methods disclosed herein can be used for treating a disease orcondition, for example, for pain, for hormone disorder, or for rapidonset treatment of headache, including migraine, e.g., acute treatmentof migraine with or without aura.

Compositions disclosed herein can comprise a) an active agent, whereinthe total dose of an active agent administered is 0.1-10.0 mg; b) amicrocrystalline cellulose comprising at least 15% of the total weightof the composition. In some cases, a mean T_(max) of an active agentafter administration of the powder composition may be about 1-120minutes. The presented methods can comprise: intranasally administeringto a human a powder composition comprising: a) an active agent, whereinthe total dose of an active agent administered is 0.1-10.0 mg; b)microcrystalline cellulose comprising at least 15% of the total weightof the composition.

Compositions and methods disclosed herein may further comprise at leastone of the following: a) wherein a mean T_(max) of an active agent afteradministration of the powder composition is about 1 to about 120minutes; b) wherein a (AUC_(0-30 min)/AUC_(0-inf))×100% of an activeagent after administration of the powder composition is greater than2.5%; c) wherein a (AUC_(0-30 min)/AUC_(0-inf))×100% of an active agentafter administration of the powder composition is greater than 2.5% to25%; d) wherein a (AUC_(0-60 min)/AUC_(0-inf))×100% of an active agentafter administration of the powder composition is greater than 10%; e)wherein a (AUC_(0-60 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 10% to 45%; f)wherein a (AUC_(0-120 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 25%; g) whereina (AUC_(0-120 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 25% to 75%; h)wherein when the powder composition is administered to a primate,preferably a monkey, and preferably a Cynomolgus monkey, a(AUC_(0-30 min)/AUC_(0-inf))×100% is greater than 10%; i) wherein whenthe powder composition is administered to a primate, preferably amonkey, and preferably a Cynomolgus monkey, a(AUC_(0-60 min)/AUC_(0-inf))×100% is greater than 20%; j) wherein whenthe powder composition is administered to a primate, preferably amonkey, and preferably a Cynomolgus monkey, a(AUC_(0-120 min)/AUC_(0-inf))×100% is greater than 40%. The mean T_(max)after administration of the powder composition can be measured from aprimate, preferably a monkey, and preferably a Cynomolgus monkey.

In some instances, a (AUC_(0-30 min)/AUC_(0-inf))×100% of an activeagent after administration of the powder composition is greater than2.5%, for example, greater than 2.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%,25%, or 30%. In some instances, the (AUC_(0-30 min)/AUC_(0-inf))×100% ofan active agent after administration of the powder composition isgreater than 2.5% to 75%, for example, 2.5% to 50%, 2.5% to 25%, 2.5% to15%, or 2.5% to 5%. In some instances, a(AUC_(0-60 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 5%, forexample, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, or 60%. In some instances, the(AUC_(0-60 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 5% to 75%, forexample, 5% to 50%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to45%, 10% to 25%, 10% to 15%, 15% to 50%, 15% to 25%, or 25% to 50%. Insome instances, a (AUC_(0-120 min)/AUC_(0-inf))×100% of an active agentafter administration of the powder composition is greater than 5%, forexample, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some instances, the(AUC_(0-120 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 15% to 75%, forexample, 15% to 75%, 15% to 50%, 15% to 25%, 25% to 75%, 25% to 50%, or50% to 75%.

In some instances, when the powder composition is administered to aprimate, preferably a monkey, and preferably a Cynomolgus monkey, a(AUC_(0-30 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 2.5%, forexample, greater than 2.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or30%. In some instances, the (AUC_(0-30 min)/AUC_(0-inf))×100% of anactive agent after administration of the powder composition is greaterthan 2.5% to 75%, for example, 2.5% to 50%, 2.5% to 25%, 2.5% to 15%, or2.5% to 5%. For example, the (AUC_(0-30 min)/AUC_(0-inf))×100% of anactive agent after administration of the powder composition may be about10%. In some instances, when the powder composition is administered to aprimate, preferably a monkey, and preferably a Cynomolgus monkey, a(AUC_(0-60 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 5%, forexample, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, or 60%. In some instances, the(AUC_(0-60 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 5% to 75%, forexample, 5% to 50%, 5% to 25%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to45%, 10% to 25%, 10% to 15%, 15% to 50%, 15% to 25%, or 25% to 50%. Forexample, the (AUC_(0-60 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition may be about 20%. In someinstances, when the powder composition is administered to a primate,preferably a monkey, and preferably a Cynomolgus monkey, a(AUC_(0-120 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 5%, forexample, greater than 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some instances, the(AUC_(0-120 min)/AUC_(0-inf))×100% of an active agent afteradministration of the powder composition is greater than 15% to 75%, forexample, 15% to 75%, 15% to 50%, 15% to 25%, 25% to 75%, 25% to 50%, or50% to 75%. For example, the (AUC_(0-120 min)/AUC_(0-inf))×100% of anactive agent after administration of the powder composition may be about40%.

Compositions disclosed herein can comprise a) an active agent, whereinthe total dose of DHE administered is 0.1-10.0 mg; and b) amicrocrystalline cellulose comprising at least 15% of the total weightof the composition. In some cases, a mean T_(max) of an active agentafter administration of the powder composition is about 1-120 minutes.The presented methods can comprise: intranasally administering to ahuman a powder composition comprising: a) an active agent, wherein thetotal dose of an active agent administered is 0.1-10.0 mg; b) amicrocrystalline cellulose comprises at least 15% of the total weight ofthe composition; wherein a mean T_(max) of an active agent afteradministration of the powder composition is about 1-120 minutes. Themean T_(max) after administration of the powder composition can bemeasured from a human subject.

In some instances, the methods and compositions comprise a mean T_(max)of an active agent after administration of the composition of at leastabout 1 minutes, for example, at least about 1 minute, 2 minutes, 3minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60minutes, 90 minutes, or 120 minutes. The mean T_(max) of an active agentafter administration of the composition can be about 1 to about 120minutes, for example, about 1-120 minutes, about 1-90 minutes, about1-60 minutes, about 1-50 minutes, 1-40 minutes, 1-30 minutes, 1-20minutes, 1-10 minutes, 1-5 minutes, about 1-2 minutes, about 5-120minutes, about 5-90 minutes, about 5-60 minutes, about 5-50 minutes,5-40 minutes, 5-30 minutes, 5-25 minutes, 5-20 minutes, 5-10 minutes,about 10-120 minutes, about 10-90 minutes, about 10-60 minutes, about10-50 minutes, 10-40 minutes, 10-30 minutes, 10-20 minutes, about 20-120minutes, about 20-90 minutes, about 20-60 minutes, about 20-50 minutes,20-40 minutes, 20-30 minutes, about 30-120 minutes, about 30-90 minutes,about 30-60 minutes, about 30-50 minutes, 30-40 minutes, about 40-120minutes, about 40-90 minutes, about 40-60 minutes, 40-50 minutes, about50-120 minutes, about 50-90 minutes, about 50-60 minutes, about 60-120minutes, about 60-90 minutes, or about 90-120 minutes. The mean T_(max)after administration of the powder composition can be measured from aprimate, preferably a monkey, and preferably a Cynomolgus monkey. Themean T_(max) after administration of the powder composition can bemeasured from a human subject.

In some instances, the methods and compositions comprise a mean C_(max)of an active agent after administration of the composition of at leastabout 0.01 nanogram/milliliter (ng/mL), for example, at least about 0.01ng/mL, 0.1 ng/mL, 0.2 ng/mL, 0.3 ng/mL, 0.4 ng/mL, 0.5 ng/mL, 0.6 ng/mL,0.7 ng/mL, 0.8 ng/mL, 0.9 ng/mL, 1 ng/mL, 1.5 ng/mL, 2 ng/mL, 2.5 ng/mL,3 ng/mL, 3.5 ng/mL, 4 ng/mL, 4.5 ng/mL, 5 ng/mL, 5.5 ng/mL, 6 ng/mL, 6.5ng/mL, 7 ng/mL, 7.5 ng/mL, 8 ng/mL, 8.5 ng/mL, 9 ng/mL, 9.5 ng/mL, 10ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng/mL, 40ng/mL, 45 ng/mL, 50 ng/mL, 55 ng/mL, 60 ng/mL, 65 ng/mL, 70 ng/mL, 75ng/mL, 80 ng/mL, 85 ng/mL, 90 ng/mL, 95 ng/mL, 100 ng/mL, 110 ng/mL, 120ng/mL, 130 ng/mL, 140 ng/mL, or 150 ng/mL. The mean C_(max) of an activeagent after administration of the composition can be about 0.1 to about150 ng/mL, for example, about 0.1-150 ng/mL, 0.1-130 ng/mL, 0.1-110ng/mL, 0.1-90 ng/mL, 0.1-70 ng/mL, 0.1-50 ng/mL, 0.1-30 ng/mL, 0.1-10ng/mL, 0.1-5 ng/mL, 0.1-1.0 ng/mL, 0.1-0.5 ng/mL, 1-150 ng/mL, 1-130ng/mL, 1-110 ng/mL, 1-90 ng/mL, 1-70 ng/mL, 1-50 ng/mL, 1-30 ng/mL, 1-10ng/mL, 1-5 ng/mL, 5-150 ng/mL, 5-130 ng/mL, 5-110 ng/mL, 5-90 ng/mL,5-70 ng/mL, 5-50 ng/mL, 5-30 ng/mL, 5-10 ng/mL, 10-150 ng/mL, 10-130ng/mL, 10-110 ng/mL, 10-90 ng/mL, 10-70 ng/mL, 10-50 ng/mL, 10-30 ng/mL,30-150 ng/mL, 30-130 ng/mL, 30-110 ng/mL, 30-90 ng/mL, 30-70 ng/mL,30-50 ng/mL, 50-150 ng/mL, 50-130 ng/mL, 50-110 ng/mL, 50-90 ng/mL,50-70 ng/mL, 70-150 ng/mL, 70-130 ng/mL, 70-110 ng/mL, 70-90 ng/mL,90-150 ng/mL, 90-130 ng/mL, 90-110 ng/mL, 110-150 ng/mL, 110-130 ng/mL,or 130-150 ng/mL. The mean C_(max) after administration of the powdercomposition can be measured from a primate, preferably a monkey, andpreferably a Cynomolgus monkey. The mean C_(max) after administration ofthe powder composition can be measured from a human subject.

In some instances, the methods and compositions comprise a meanAUC_(0-inf) of an active agent after administration of the compositionof at least about 0.5 nanogram·hour/milliliter (ng·h/mL), for example,at least about 0.5 ng·h/mL, 1 ng·h/mL, 2 ng·h/mL, 3 ng·h/mL, 4 ng·h/mL,5 ng·h/mL, 6 ng·h/mL, 7 ng·h/mL, 8 ng·h/mL, 9 ng·h/mL, 10 ng·h/mL, 20ng·h/mL, 30 ng·h/mL, 40 ng·h/mL, 50 ng·h/mL, 60 ng·h/mL, 70 ng·h/mL, 80ng·h/mL, 90 ng·h/mL, 100 ng·h/mL, 200 ng·h/mL, 300 ng·h/mL, 400 ng·h/mL,500 ng·h/mL, 600 ng·h/mL, or 700 ng·h/mL. The mean AUC_(0-inf) of anactive agent after administration of the composition can be about 0.5 toabout 700 ng·h/mL, for example, about 0.5-700 ng·h/mL, 0.5-500 ng·h/mL,0.5-300 ng·h/mL, 0.5-100 ng·h/mL, 0.5-80 ng·h/mL, 0.5-60 ng·h/mL, 0.5-40ng·h/mL, 0.5-20 ng·h/mL, 0.5-10 ng·h/mL, 0.5-5 ng·h/mL, 0.5-2 ng·h/mL,0.5-1 ng·h/mL, 1-700 ng·h/mL, 1-500 ng·h/mL, 1-300 ng·h/mL, 1-100ng·h/mL, 1-80 ng·h/mL, 1-60 ng·h/mL, 1-40 ng·h/mL, 1-20 ng·h/mL, 1-10ng·h/mL, 1-5 ng·h/mL, 10-700 ng·h/mL, 10-500 ng·h/mL, 10-300 ng·h/mL,10-100 ng·h/mL, 10-80 ng·h/mL, 10-60 ng·h/mL, 10-40 ng·h/mL, 10-20ng·h/mL, 20-700 ng·h/mL, 20-500 ng·h/mL, 20-300 ng·h/mL, 20-100 ng·h/mL,20-80 ng·h/mL, 20-60 ng·h/mL, 20-40 ng·h/mL, 40-700 ng·h/mL, 40-500ng·h/mL, 40-300 ng·h/mL, 40-100 ng·h/mL, 40-80 ng·h/mL, 40-60 ng·h/mL,60-700 ng·h/mL, 60-500 ng·h/mL, 60-300 ng·h/mL, 60-100 ng·h/mL, 60-80ng·h/mL, 80-700 ng·h/mL, 80-500 ng·h/mL, 80-300 ng·h/mL, 80-100 ng·h/mL,100-700 ng·h/mL, 100-500 ng·h/mL, 100-300 ng·h/mL, 300-700 ng·h/mL,300-500 ng·h/mL, or 500-700 ng·h/mL. The mean AUC_(0-inf) afteradministration of the powder composition can be measured from a primate,preferably a monkey, and preferably a Cynomolgus monkey. The meanAUC_(0-inf) after administration of the powder composition can bemeasured from a human subject.

In some instances, the methods and compositions comprise a meanAUC_(0-t) of an active agent after administration of the composition ofat least about 0.5 ng·h/mL, for example, at least about 0.5 ng·h/mL, 1ng·h/mL, 2 ng·h/mL, 3 ng·h/mL, 4 ng·h/mL, 5 ng·h/mL, 6 ng·h/mL, 7ng·h/mL, 8 ng·h/mL, 9 ng·h/mL, 10 ng·h/mL, 20 ng·h/mL, 30 ng·h/mL, 40ng·h/mL, 50 ng·h/mL, 60 ng·h/mL, 70 ng·h/mL, 80 ng·h/mL, 90 ng·h/mL, 100ng·h/mL, 200 ng·h/mL, 300 ng·h/mL, 400 ng·h/mL, 500 ng·h/mL, 600ng·h/mL, or 700 ng·h/mL. The mean AUC_(0-inf) of an active agent afteradministration of the composition can be about 0.5 to about 700 ng·h/mL,for example, about 0.5-700 ng·h/mL, 0.5-500 ng·h/mL, 0.5-300 ng·h/mL,0.5-100 ng·h/mL, 0.5-80 ng·h/mL, 0.5-60 ng·h/mL, 0.5-40 ng·h/mL, 0.5-20ng·h/mL, 0.5-10 ng·h/mL, 0.5-5 ng·h/mL, 0.5-2 ng·h/mL, 0.5-1 ng·h/mL,1-700 ng·h/mL, 1-500 ng·h/mL, 1-300 ng·h/mL, 1-100 ng·h/mL, 1-80ng·h/mL, 1-60 ng·h/mL, 1-40 ng·h/mL, 1-20 ng·h/mL, 1-10 ng·h/mL, 1-5ng·h/mL, 10-700 ng·h/mL, 10-500 ng·h/mL, 10-300 ng·h/mL, 10-100 ng·h/mL,10-80 ng·h/mL, 10-60 ng·h/mL, 10-40 ng·h/mL, 10-20 ng·h/mL, 20-700ng·h/mL, 20-500 ng·h/mL, 20-300 ng·h/mL, 20-100 ng·h/mL, 20-80 ng·h/mL,20-60 ng·h/mL, 20-40 ng·h/mL, 40-700 ng·h/mL, 40-500 ng·h/mL, 40-300ng·h/mL, 40-100 ng·h/mL, 40-80 ng·h/mL, 40-60 ng·h/mL, 60-700 ng·h/mL,60-500 ng·h/mL, 60-300 ng·h/mL, 60-100 ng·h/mL, 60-80 ng·h/mL, 80-700ng·h/mL, 80-500 ng·h/mL, 80-300 ng·h/mL, 80-100 ng·h/mL, 100-700ng·h/mL, 100-500 ng·h/mL, 100-300 ng·h/mL, 300-700 ng·h/mL, 300-500ng·h/mL, or 500-700 ng·h/mL. The mean AUC_(0-inf) after administrationof the powder composition can be measured from a primate, preferably amonkey, and preferably a Cynomolgus monkey. The mean AUC_(0-inf) afteradministration of the powder composition can be measured from a humansubject. The measurement can be taken 5 minutes, 10 minutes, 20 minutes,30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240minutes, 300 minutes, 360 minutes, 420 minutes, or 480 minutes.

In some instances, the methods and compositions comprise a mean T_(1/2)of an active agent after administration of the composition of at leastabout 10 minutes, for example, at least about 10 minutes, 20 minutes, 30minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90minutes, 100 minutes, 120 minutes, 150 minutes, 200 minutes, 250minutes, or 300 minutes. The mean T_(1/2) of an active agent afteradministration of the composition can be about 10 to about 300 minutes,for example, about 10-300 minutes, 10-250 minutes, 10-200 minutes,10-150 minutes, 10-120 minutes, 10-100 minutes, 10-80 minutes, 10-60minutes, 10-40 minutes, 10-20 minutes, 20-300 minutes, 20-250 minutes,20-200 minutes, 20-150 minutes, 20-120 minutes, 20-100 minutes, 20-80minutes, 20-60 minutes, 20-40 minutes, 40-300 minutes, 40-250 minutes,40-200 minutes, 40-150 minutes, 40-120 minutes, 40-100 minutes, 40-80minutes, 40-60 minutes, 60-300 minutes, 60-250 minutes, 60-200 minutes,60-150 minutes, 60-120 minutes, 60-100 minutes, 60-80 minutes, 80-300minutes, 80-250 minutes, 80-200 minutes, 80-150 minutes, 80-120 minutes,80-100 minutes, 100-300 minutes, 100-250 minutes, 100-200 minutes,100-150 minutes, 100-120 minutes, 120-300 minutes, 120-250 minutes,120-200 minutes, 120-150 minutes, 150-300 minutes, 150-250 minutes,150-200 minutes, 200-300 minutes, 200-250 minutes, or 250-300 minutes.For example, the mean T_(1/2) of an active agent after administration ofthe composition is about 100 to about 300 minutes. The mean T_(1/2)after administration of the powder composition can be measured from amonkey (e.g., Cynomolgus monkeys). The mean T_(1/2) after administrationof the powder composition can be measured from a human subject.

In some instances, the methods presented herein comprising intranasallyadministering to a human a powder composition comprising an activeagent, wherein the method further comprises at least one of thefollowing: wherein a mean T_(max) of an active agent afteradministration of the composition is about 2 to about 50 minutes; b)wherein a mean C_(max) of an active agent after administration of thecomposition is about 0.1 to about 150 ng/mL; c) wherein a meanAUC_(0-inf) of an active agent after administration of the compositionis about 1 to about 700 ng·h/mL; d) wherein a mean T_(1/2) of an activeagent after administration of the composition is about 100 to about 300minutes. In some instances, the mean T_(max) of an active agent afteradministration of the composition is about 2 to about 50 minutes. Insome instances, the mean C_(max) of an active agent after administrationof the composition is about 0.1 to about 150 ng/mL. In some instances,the mean AUC_(0-inf) of an active agent after administration of thecomposition is about 1 to about 700 ng·h/mL. In some instances, the meanT_(1/2) of an active agent after administration of the composition isabout 100 to about 300 minutes. The mean T_(max), C_(max), AUC_(0-inf),and/or T_(1/2) after administration of the powder composition can bemeasured from a primate, preferably a monkey, and preferably aCynomolgus monkey. The mean T_(max), C_(max), AUC_(0-inf), and/orT_(1/2) after administration of the powder composition can be measuredfrom a human subject.

In one case of an active agent, the mean T_(max) may be about 10 toabout 30 minutes, the mean C_(max) can be about 0.5 to about 6 ng/mL,the mean AUC_(0-inf) can be about 1 to about 15 ng·h/mL, and the meanT_(1/2) can be about 100 to about 300 minutes. In another case, the meanT_(max) may be about 10 to about 50 minutes, the mean C_(max) can beabout 1 to about 15 ng/mL, the mean AUC_(0-inf) can be about 10 to about50 ng·h/mL, and the mean T_(1/2) can be about 100 to about 300 minutes.In another case of an active agent, the mean T_(max) may be about 10 toabout 50 minutes, the mean C_(max) can be about 2 to about 20 ng/mL, themean AUC_(0-inf) can be about 15 to about 110 ng·h/mL, and the meanT_(1/2) can be about 100 to about 300 minutes. In another case of anactive agent, the mean T_(max) may be about 10 to about 50 minutes, themean C_(max) can be about 2 to about 50 ng/mL, the mean AUC_(0-inf) canbe about 15 to about 200 ng·h/mL, and the mean T_(1/2) can be about 100to about 300 minutes. The mean T_(max), C_(max), AUC_(0-inf), and/orT_(1/2) after administration of the powder composition can be measuredfrom a primate, preferably a monkey, and preferably a Cynomolgus monkey.The mean T_(max), C_(max), AUC_(0-inf), and/or T_(1/2) afteradministration of the powder composition can be measured from a humansubject.

In some cases, the powder composition is administered such that theintersubject variability in an active agent C_(max) can be less than50%. For example, the intersubject variability in an active agentC_(max) may be less than 50%, 30%, 25%, 20%, 15%, 10%, or 5%. In somecases, the powder composition can be administered such that theintersubject variability in an active agent T_(max) is less than 30%.For example, the intersubject variability in an active agent T_(max) canbe less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the powdercomposition is administered such that the intersubject variability inDHE AUC_(0-inf) may be less than 30%. For example, the intersubjectvariability in an active agent AUC_(0-inf) can be less than 30%, 25%,20%, 15%, 10%, or 5%. In some cases, the powder composition isadministered such that the intersubject variability in an active agentT_(1/2) can be less than 30%. For example, the intersubject variabilityin an active agent T_(1/2) may be less than 30%, 25%, 20%, 15%, 10%, or5%. The intersubject variability in an active agent T_(max), C_(max),AUC_(0-inf), and/or T_(1/2) after administration of the powdercomposition can be measured from primates, preferably monkeys, andpreferably a Cynomolgus monkeys. The intersubject variability in anactive agent T_(max), C_(max), AUC_(0-inf), and/or T_(1/2) afteradministration of the powder composition can be measured from humansubjects.

In some cases, a pharmacokinetic parameter disclosed herein isdetermined with an analysis of a blood sample or plasma sample collectedat one or more time points of about: 2, 5, 10, 15, 20, 30, 45, 60, 120,or 180 minutes after intranasal administration. In some instances, theanalysis comprises a measurement of a plasma concentration of DHE,8′-hydroxy-DHE, or a combination thereof in the blood sample or plasmasample. In some instances, the analysis is conducted with liquidchromatography (LC), mass spectrometry (MS), or a combination thereof.In some instances, the analysis is conducted with a LC/MS/MS method.

In some instances, powder compositions herein further comprise anadditional active agent disclosed herein, e.g., caffeine, for example,anhydrous caffeine. In some instances, the powder compositions utilizedas part of the methods of treating headache, including migraine,comprise about 1-60%, about 1-25%, about 10-60%, or about 10-25% of anactive agent. In some instances, the powder compositions utilized aspart of the methods of treating headache, including migraine, compriseabout 1%, about 5%, about 6%, about 10%, about 12%, about 20%, about23%, about 39%, about 48%, about 50%, or about 58% of an active agent.

In some instances, an average particle size of the active agent is about10-100 μm, for example, about 10 to 75 μm, about 10 to 50 μm, about10-30 μm, about 10-20 μm, about 15-20 μm, about 10 μm, about 15 μm,about 16 μm, about 17 μm, about 18 μm, about 19 μm, or about 20 μm. Insome instances, not less than 90% of the active agent's particles in thepowder compositions presented herein have a diameter less than 150 μm,and not more than 5% of the caffeine particles in the powder compositionhave a diameter less than 10 μm. In some instances, the overall averageparticle size of the active agent's particles in the powder compositionspresented herein is about 15 to about 30 μm, about 18 to about 25 μm,about 18 to about 20 μm, or about 20 μm.

In some instances, a powder composition comprises about an active agent(e.g., about: 0.5 mg, 1.0 mg, 1.5 mg, 2 mg) and is administered suchthat the mean T_(max) of an active agent is about 10-30 minutes. In someinstances, the powder composition is administered such that the meanT_(max) of an active agent is about 2-50 minutes. In some instances, thepowder composition is administered such that the mean T_(max) of anactive agent is about 2-30 minutes. In some instances, the powdercomposition is administered such that the mean C_(max) of an activeagent is about 0.5-10 ng/mL. In some instances, the powder compositionis administered such that the mean AUC_(0-inf) of an active agent isabout 1-15 ng·h/mL. In some instances, the powder composition isadministered such that the mean T_(max) of an active agent is about 2-30minutes, the mean C_(max) of an active agent is about 0.5-6 ng/mL, themean AUC_(0-inf) of an active agent is about 1-15 ng·h/mL, and the meanT_(1/2) of an active agent is about 100-300 minutes. In some instances,the intersubject variability in an active agent C_(max) is less than30%.

In some instances, a powder composition comprises an active agent (e.g.,DHE or a salt thereof, DHE mesylate). In some instances, the powdercomposition is administered to a single nostril of the human having aheadache, including migraine. In some instances, a portion of the powdercomposition is administered to each nostril of the human having aheadache, e.g., migraine. For example, in some instances, about half ofthe powder composition is administered to one nostril and about half ofthe powder composition is administered to the other nostril of the humanin need thereof.

In some instances, a total dose of an active agent administered is about0.1-6.0 mg. In some instances, the total dose of an active agentadministered is about 0.5-6.0 mg. In some instances, the total dose ofan active agent administered is about 1.0-4.0 mg. In some instances, thetotal dose of an active agent administered is about 1.0-5.0 mg. In someinstances, the total dose of an active agent administered is about 0.1mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0mg, about 4.0 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg. In someinstances, the total dose is administered into a single nostril. In someinstances, a portion of the total dose is administered into eachnostril. In some instances, about half of the total dose is administeredinto one nostril and the remaining half is administered into the othernostril.

Excipients

In some cases, a composition disclosed herein comprises one or moreexcipients, e.g., different substance, or same substance but differentsizes. In some instances, the excipient comprises a carrier, e.g.,water-insoluble polysaccharide or oligosaccharide. In some instances,the carrier is selected from a group consisting of cellulose acetate,cellulose acetate butyrate, cellulose acetate propionate, celluloseacetate phthalate, chitosan, β-cyclodextrin, ethyl cellulose,hydroxypropylmethyl cellulose phthalate (HPMCP), microcrystallinecellulose, starch, and any combination thereof. In some instances, theexcipient comprises a thickening agent, e.g., a water-solublepolysaccharide. In some instances, the thickening agent is selected fromthe group consisting of hydroxy propyl methyl cellulose (HPMC), acacia,alginic acid, colloidal silicone dioxide, carboxymethylcellulosecalcium, gelatin, hydroxy propyl cellulose, hydroxyl propyl cellulose(hypromellose), methyl cellulose, sucrose, sodium alginate, sodiumcarboxy methyl cellulose, and any combination thereof. In someinstances, the excipient comprises a first excipient (any excipientdisclosed herein) and a second excipient (any excipient disclosedherein). In some instances, the excipient comprises a carrier (e.g.,microcrystalline cellulose) and a thickening agent (e.g., HPMC).

In some instances, particles comprise a thickening agent that is presentin an amount of about: 0.1-0.5%, 0.05-1%, 0.05-2%, 0.05-3%, 0.05-4%,0.05-5%, 4-6%, 3-7%, 2-8%, 1-10%, or 1-20% by weight based on a weightof the particles or a pharmaceutical powder composition, for exampleabout: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3,3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 percent. In some instances, particles comprise microcrystallinecellulose that is present in an amount of about: 10-95%, 10-75%, 15-55%,20-75%, 35-75%, or 40-75% by weight based on a weight of the particlesor a pharmaceutical powder composition, for example about: 10%, 20%,30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95%. In some instances,particles comprise a sugar alcohol that is present in an amount ofabout: 10-95%, 10-75%, 15-55%, 20-75%, 35-75%, or 40-75% by weight basedon a weight of the particles or a pharmaceutical powder composition, forexample about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or95%. In some instances, particles comprise the pH adjusting agent thatis present in an amount of about: 10-20%, 20-30%, 5-25%, 15-35%, or5-40% by weight based on a weight of the particles or a pharmaceuticalpowder composition, for example about: 5%, 6%, 7%, 8%, 9%, 10%, 15%,20%, 25%, 30%, 35%, or 40%.

In some instances, a particle or composition disclosed herein comprisesa pH adjusting agent. In some instances, the pH adjusting agent isselected from the group consisting of ascorbic acid, sodium ascorbate,tartaric acid, sodium tartrate, potassium tartrate, calcium tartrate,lithium tartrate, citric acid, sodium citrate, potassium citrate,calcium citrate, lithium citrate, phosphoric acid, sodiumdihydrogenphosphate, sodium monohydrogenphosphate, lithium phosphate,potassium phosphate, calcium phosphate, sodium carbonate, sodiumhydrogencarbonate, lactic acid, sodium lactate, potassium lactate,calcium lactate, acetic acid, sodium acetate, potassium acetate, calciumacetate, propionic acid, sulphuric acid, sodium sulphate, potassiumsulphate, boric acid, sodium borate, maleic acid, lithium maleate,sodium maleate, potassium maleate, calcium maleate, succinic acid,lithium succinate, sodium succinate, potassium succinate, calciumsuccinate, fumaric acid, glutamic acid, formic acid, malic acid,hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide,triethanolamine, diisopropanolamine, ammonia solution, monoethanoleamine, diethanoleamine, triethanoleamine meglumine, sodium citrate,sodium bicarbonate, potassium bicarbonate, and any combination thereof.In some instances, a pH adjusting agent disclosed herein is acetic acid;adipic acid; ammonium aluminum sulphate; ammonium bicarbonate; ammoniumcarbonate; ammonium citrate, dibasic; ammonium citrate, monobasic;ammonium hydroxide; ammonium phosphate, dibasic; ammonium phosphate,monobasic; calcium acetate; calcium acid pyrophosphate; calciumcarbonate; calcium chloride; calcium citrate; calcium fumarate; calciumgluconate; calcium hydroxide; calcium lactate; calcium oxide; calciumphosphate, dibasic; calcium phosphate, monobasic; calcium phosphate,tribasic; calcium sulphate; carbon dioxide; citric acid; cream oftartar; fumaric acid; gluconic acid; glucono-delta-lactone; hydrochloricacid; lactic acid; magnesium carbonate; magnesium citrate; magnesiumfumarate; magnesium hydroxide; magnesium oxide; magnesium phosphate;magnesium sulphate; malic acid; manganese sulphate; metatartaric acid;phosphoric acid; potassium acid tartrate; potassium aluminum sulphate;potassium bicarbonate; potassium carbonate; potassium chloride;potassium citrate; potassium fumarate; potassium hydroxide; potassiumlactate; potassium phosphate, dibasic; potassium phosphate, tribasic;potassium sulphate; potassium tartrate; potassium tripolyphosphate;sodium acetate; sodium acid pyrophosphate; sodium acid tartrate; sodiumaluminum phosphate; sodium aluminum sulphate; sodium bicarbonate; sodiumbisulphate; sodium carbonate; sodium citrate; sodium fumarate; sodiumgluconate; sodium hexametaphosphate; sodium hydroxide; sodium lactate;sodium phosphate, dibasic; sodium phosphate, monobasic; sodiumphosphate, tribasic; sodium potassium hexametaphosphate; sodiumpotassium tartrate; sodium potassium tripolyphosphate; sodiumpyrophosphate, tetrabasic; sodium tripolyphosphate; sulphuric acid;sulphurous acid; tartaric acid; or any combination thereof.

In some instances, a particle or composition disclosed herein comprisesa sugar alcohol. In some instances, the sugar alcohol is selected fromthe group consisting of mannitol, glycerol, galactitol, fucitol,inositol, volemitol, maltotriitol, maltoetetraitol, polyglycitol,erythritol, threitol, ribitol, arabitol, xylitol, allitol, dulcitol,glucitol, sorbitol, altritol, iditol, maltitol, lactitol, isomalt, andany combination thereof. In some instances, the sugar alcohol has 3, 4,5, 6, 7, 12, 18, or 24 carbons.

In some instances, compositions may further comprise a fluidizing agent.For example, the fluidizing agent is a metal salt (e.g., a calcium salt)or a phosphate salt. In some instances, the fluidizing agent is acalcium phosphate salt, e.g., tribasic calcium phosphate. The tribasiccalcium phosphate can be about 0.1% to about 5.0% of the total weight ofthe powder composition, for example about: 0.1%-5%, 0.1%-4%, 0.1%-3%,0.1%-2%, 0.1%-1%, 0.1%-0.5%, 0.5%-5%, 0.5%-4%, 0.5%-3%, 0.5%-2%,0.5%-1%, 1%-5%, 1%-4%, 1%-3%, 1%-2%, 2%-5%, 2%-4%, 2%-3%, 3%-5%, 3%-4%,or 4%-5% of the total weight of the powder composition. In someinstances, the tribasic calcium phosphate is about 0.5% to about 1.0% ofthe total weight of the powder composition. In some instances, thetribasic calcium phosphate is about 0.5% to about 1.5% of the totalweight of the powder composition. In some instances, the tribasiccalcium phosphate is about 0.8% of the total weight of the powdercomposition.

In some cases, an excipient has an average particle size of about 100 μmor less, e.g., about: 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm,60 μm, 55 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10μm, 5 μm or less. In some instances, a composition herein may comprise afirst excipient with an average particle diameter size of about 30 μm orless, and a second excipient with an average particle size diameter ofabout 30 to about 100 μm. The first excipient may have an averageparticle diameter size of about 30 μm or less, for example, about: 30-25μm, 30-20 μm, 30-15 μm, 30-10 μm, 30-5 μm, 25-20 μm, 25-15 μm, 25-10 μm,25-5 μm, 20-15 μm, 20-10 μm, 20-5 μm, 15-10 μm, 15-5 μm or 10-5 μm. Insome instances, the first excipient has an average particle diametersize of about 15-30 μm. In some instances, the first excipient has anaverage particle diameter size of about 18-20 μm. In some instances, thefirst excipient has an average particle diameter size of about 20 μm.The second excipient may have an average particle diameter size of about30 to about 100 μm, for example, about: 30-90 μm, 30-80 μm, 30-70 μm,30-60 μm, 30-50 μm, 30-40 μm, 40-90 μm, 40-80 μm, 40-70 μm, 40-60 μm,40-50 μm, 50-90 μm, 50-80 μm, 50-70 μm, 50-60 μm, 60-90 μm, 60-80 μm,60-70 μm, 70-90 μm, 70-80 μm, or 80-90 μm. In some instances, the secondexcipient has an average particle diameter size of about 45-65 μm. Insome instances, the second excipient has an average particle diametersize of about 45-55 μm. In some instances, the second excipient has anaverage particle diameter size of about 50-55 μm. In some instances, thesecond excipient has an average particle diameter size of about 50 μm.In some instances, the first excipient has an average particle diametersize of about 15 to about 30 μm and the second excipient has an averageparticle diameter size of about 45 to about 65 μm. In some instances,the first excipient has an average particle size of about 20 μm and thesecond excipient has an average particle size diameter of about 50 toabout 55 μm. In some instances, the first excipient has an averageparticle diameter size of about 20 μm, and the second excipient has anaverage particle size diameter of about 50 μm. In some cases, theexcipient is substantially free of particles with an average particlediameter size of about 31 to about 44 μm. In some instances, theexcipient is substantially free of particles with an average particlediameter size of about 31 to about 49 μm. In some cases, substantiallyfree of particles with an average particle diameter size means less than15%, 10%, 5%, or 2% of all the particles fall into the given range.

In some cases, one or more excipient(s) (e.g., microcrystallinecellulose, HPMC, mannitol, TCP) may comprise at least about 5% of thetotal weight of the powder composition, for example, at least about: 5%,6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the total weight of thepowder composition. The excipient(s) may comprise about 15% to about 99%of the total weight of the powder composition, for example, about:15%-99%, 20%-99%, 30%-99%, 40-99%, 50-99%, 60-99%, 70-99%, 80-99%,90-99%, 15%-90%, 20%-90%, 30%-90%, 40-90%, 50-90%, 60-90%, 70-90%,80-90%, 15%-80%, 20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70-80%,15%-70%, 20%-70%, 30%-70%, 40-70%, 50-70%, 60-70%, 15%-60%, 20%-60%,30%-60%, 40-60%, 50-60%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 15%-40%,20%-40%, 30%-40%, 15%-30%, 20%-30%, or 15-20% of the total weight of thepowder composition. In some instances, the first excipient comprisesabout 10 to about 90% of the total weight of the powder composition, forexample, about: 10%-90%, 15%-90%, 20%-90%, 30%-90%, 40-90%, 50-90%,60-90%, 70-90%, 80-90%, 10%-80%, 15%-80%, 20%-80%, 30%-80%, 40-80%,50-80%, 60-80%, 70-80%, 10%-70%, 15%-70%, 20%-70%, 30%-70%, 40-70%,50-70%, 60-70%, 10%-60%, 15%-60%, 20%-60%, 30%-60%, 40-60%, 50-60%,10%-50%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 10%-40%, 15%-40%, 20%-40%,30%-40%, 10%-30%, 15%-30%, 20%-30%, 10%-20%, 15-20%, or 10%-15% of thetotal weight of the powder composition. In some instances, the firstexcipient comprises about 70% to about 90% of the total weight of thepowder composition. In some instances, the first excipient comprisesabout 70% to about 90% of the total weight of the powder composition. Insome instances, the second excipient comprises about 5% to about 15% ofthe total weight of the powder composition, for example, about 5%-15%,5%-10%, or 10%-15% of the total weight of the powder composition. Insome instances, the second excipient comprises about 10% of the totalweight of the powder composition. For example, the first excipientcomprises about 8% to about 90% of the total weight of the composition,and the second excipient comprises about 10% of the total weight of thecomposition. In some instances, the first excipient is about 5% to about90% of the total weight of the powder composition, and the secondexcipient is about 10% of the total weight of the powder composition.

With respect to the microcrystalline cellulose component of the powdercompositions presented herein, generally, acceptable microcrystallinecellulose can include microcrystalline cellulose obtained by decomposingcellulose materials such as pulp by either or both of acid and alkalinehydrolyses, then purifying the hydrolysate, and crushing or grinding itbefore, during, or after drying. Microcrystalline cellulose of a selectaverage particle diameter size can be obtained, for example, viaappropriate processing, e.g., via fine grinding using a high-speedrotary impact mill or air attrition mill as necessary, and size sorting.In some instances, microcrystalline cellulose components utilized aspart of the microcellulose of the powder compositions presented hereincan include products available under the trade names of Ceolus® PH-F20JP(e.g., average particle size about 20-23 microns, bulk density about0.23 g/cm³, repose angle not less than 60 degrees), Ceolus® PH-301(e.g., average particle size about 50 microns, bulk density about 0.41g/cm³, repose angle about 41 degrees), Ceolus® PH-101 (e.g., averageparticle size about 50 microns, bulk density about 0.29 g/cm³, reposeangle about 45 degrees), Ceolus® PH-102 (e.g., average particle sizeabout 90 microns, bulk density about 0.3 g/cm³, repose angle about 42degrees), and Ceolus® PH-302 (available from Asahi Kasei Corporation,e.g., average particle size about 90 microns, bulk density about 0.43g/cm³, repose angle about 38 degrees), and Avicer® PH-105 (e.g., averageparticle size about 20 microns, bulk density about 0.20-0.30 g/cm³),Avicer® PH-101 (e.g., average particle size about 50 microns, bulkdensity about 0.26-0.31 g/cm³), Avicer® PH-102 (e.g., average particlesize about 100 microns, bulk density about 0.28-0.33 g/cm³), Avicer®PH-301 (e.g., average particle size about 50 microns, bulk density about0.34-0.45 g/cm³), and Avicer® PH-302 (available from FMC BiopolymerCorporation, e.g., average particle size about 100 microns, bulk densityabout 0.35-0.46 g/cm³). In some instances, powder compositions that canbe used in conjunction with the methods and compositions presentedherein can comprise Ceolus® PH-F20JP and Ceolus® PH-301.

Average particle size diameters, for example, the average particle sizediameters of the microcrystalline portions of the powder compositionsdescribed herein, can be determined using standard techniques, forexample, via a laser-diffraction particle size distribution analyzer orvia sorting methods. The average particle diameter size refers to adiameter that divides particles into two groups of equal numbers: agroup with greater diameters and a group with smaller diameters. Theaverage diameter size determined using a laser-diffraction particle sizedistribution analyzer corresponds to 50% volume in a determinedcumulative particle size distribution curve. The average particlediameter size can, for example, be determined by a sorting method thatcorresponds to 50% (W/W) on a cumulative particle size distributioncurve that can be obtained by sorting an appropriate amount of theparticle being assessed, for an appropriate time, e.g., ten minutes, onan electromagnetic sieve shaker, using standard sieves and weighing thesample remaining on each sieve.

In some instances, the microcrystalline cellulose component of thecomposition comprises a first microcrystalline cellulose portion with anaverage particle diameter size of about 30 μm or less, and a secondmicrocrystalline cellulose portion with an average particle sizediameter of about 30-100 μm. In some instances, the firstmicrocrystalline cellulose portion has an average particle diameter sizeof about 15-30 μm. In some instances, the first microcrystallinecellulose portion has an average particle diameter size of about 18-20μm. In some instances, the first microcrystalline cellulose portion hasan average particle diameter size of about 20 μm. In some instances, thesecond microcrystalline cellulose portion has an average particlediameter size of about 45-65 μm. In some instances, the secondmicrocrystalline cellulose portion has an average particle diameter sizeof about 45-55 μm. In some instances, the second microcrystallinecellulose portion has an average particle diameter size of about 50-55μm. In some instances, the second microcrystalline cellulose portion hasan average particle diameter size of about 50 μm. In some instances, thefirst microcrystalline cellulose portion has an average particlediameter size of about 20 μm, and the second microcrystalline celluloseportion has an average particle size diameter of about 50 μm. In someinstances, the first microcrystalline cellulose portion has an averageparticle diameter size of about 30 μm or less, for example, about 15-30μm, about 18-20 μm, or about 20 μm, and the second microcrystallinecellulose portion has an average particle diameter size of about 45-65μm, about 45-55 μm, about 50-55 μm, or about 50 μm.

In some instances, the microcrystalline cellulose component of thepowder composition comprises about 10 to about 99%, e.g., about 15 toabout 99%, of the total weight of the composition. In some instances,the microcrystalline cellulose component of the powder compositioncomprises about 53 to about 99%, about 76 to about 99%, about 76 toabout 97%, about 90 to about 97%, or about 90 to about 95% of the totalweight of the composition. In some instances, the microcrystallinecellulose component of the powder composition comprises about 10 toabout 98%, about 18 to about 98%, about 18 to about 91%, about 67 toabout 91%, or about 67 to about 83%. In some instances, themicrocrystalline cellulose component of the powder composition comprisesabout 53%, about 76%, about 90%, about 95%, about 97%, or about 99% ofthe total weight of the composition. In some instances, themicrocrystalline cellulose component of the powder composition comprisesabout 10%, about 18%, about 66%, about 83%, about 91%, or about 98% ofthe total weight of the composition. In some instances, the firstmicrocrystalline cellulose portion comprises about 3.0 to about 90%,e.g., about 8.0 to about 90%, of the total weight of the composition,and the second microcrystalline cellulose portion comprises about 10% ofthe total weight of the composition. In some instances, the firstmicrocrystalline cellulose portion comprises about 43 to about 89%,about 66 to about 89%, about 66 to about 87%, about 80 to about 87%, orabout 80 to about 85% of the total weight of the composition, of thetotal weight of the composition, and the second microcrystallinecellulose portion comprises about 10% of the total weight of thecomposition. In some instances, the microcrystalline cellulose componentof the powder composition comprises about 1 to about 88%, about 8 toabout 88%, about 8 to about 81%, about 57 to about 81%, or about 57 toabout 83%, and the second microcrystalline cellulose portion comprisesabout 10% of the total weight of the composition. In some instances, themicrocrystalline cellulose component of the powder composition comprisesabout 43%, about 66%, about 80%, about 85%, about 87%, or about 89% ofthe total weight of the composition, and the second microcrystallinecellulose portion comprises about 10% of the total weight of thecomposition. In some instances, the microcrystalline cellulose componentof the powder composition comprises about 1%, about 8%, about 57%, about73%, about 81%, or about 88% of the total weight of the composition, andthe second microcrystalline cellulose portion comprises about 10% of thetotal weight of the composition.

With respect to tribasic calcium phosphate (also known ashydroxyapatite), any pharmaceutically acceptable tribasic calciumphosphate can be used in conjunction with the methods and compositionspresented herein. In some instances, the tribasic calcium phosphateutilized has an average particle diameter of about 10-100 μm, forexample, about 10-75 μm, about 10-50 μm, about 10-30 μm, or about 10 μm.In some instances, not less than 90% of the tribasic calcium phosphateparticles in the powder compositions presented herein have a diameterless than 150 μm, and not more than 5% of the particles in the powdercomposition have a diameter less than 10 μm. In some instances, theoverall average particle size of the tribasic calcium phosphateparticles in the powder compositions presented herein about 15 to about30 μm, about 18 to about 25 μm, about 18 to about 20 μm, or about 20 μm.

In some instances, greater than or equal to about 90% of the tribasiccalcium phosphate particles have a diameter less than 150 μm. In someinstances, the overall average particle size of the tribasic calciumphosphate particles is about 15 to about 30 μm, about 18 to about 25 μm,about 18 to about 20 μm, or about 20 μm. In some instances, less than orequal to about 5% of the tribasic calcium phosphate particles have adiameter less than 10 μm. In some instances, for the tribasic calciumphosphate particles, greater than or equal to about 90% of the particleshave a diameter less than 150 μm; and the overall average particle sizeis about 15 to about 30 μm, about 18 to about 25 μm, about 18 to about20 μm, or about 20 μm; and less than or equal to about 5% of theparticles have a diameter less than 10 μm.

In some instances, tribasic calcium phosphate comprises at least: about0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, 2.0%, for example,0.5-1.0% of the total weight of the composition. In specific instancesof the methods of treating headache, including migraine, the tribasiccalcium phosphate comprises about 0.8% of the total weight of thecomposition.

Doses

In some cases, a total dose of a powder composition administered can beat least about 0.1 mg, for example, at least about: 0.1 mg, 0.2 mg, 0.3mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg,2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg,7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg,15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, or 50 mg. The totaldose of the powder composition administered can be about 0.1 to about 50mg, for example, about 0.1-50.0 mg, about 0.1-25.0 mg, about 0.1-20.0mg, about 0.1-15.0 mg, about 0.1-10.0 mg, about 0.1-5.0 mg, about0.1-2.0 mg, about 0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-50.0 mg, about0.2-25.0 mg, about 0.2-20.0 mg, about 0.2-15.0 mg, about 0.2-10.0 mg,about 0.2-5.0 mg, about 0.2-2.0 mg, about 0.2-1.0 mg, about 0.2-0.5 mg,about 0.5-55.0 mg, 0.5-25.0 mg, about 0.5-20.0 mg, about 0.5-15.0 mg,about 0.5-10.0 mg, about 0.5-5.0 mg, about 0.5-2.0 mg, about 0.5-1.0 mg,about 1.0-25.0 mg, about 1.0-50.0 mg, about 1.0-20.0 mg, about 1.0-15.0mg, about 1.0-10.0 mg, about 1.0-5.0 mg, about 1.0-2.0 mg, about2.0-50.0 mg, about 2.0-25.0 mg, about 2.0-20.0 mg, about 2.0-15.0 mg,about 2.0-10.0 mg, about 2.0-5.0 mg, about 5.0-25.0 mg, about 5.0-20.0mg, about 5.0-15.0 mg, about 5.0-10.0 mg, about 10.0-50.0 mg, about0.5-25.0 mg, about 10.0-20.0 mg, about 10.0-15.0 mg, about 15.0-25.0 mg,or about 15.0-20.0 mg. For example, the total dose of the powdercomposition administered is about 25 mg.

In some cases, a powder composition comprises a total dose of an activeagent administered of at least about 0.1 mg, for example, at leastabout: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg,0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg,5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10mg. The powder composition may comprise a total dose of an active agentadministered at about 0.1 to about 10.0 mg, for example, about 0.1-10.0mg, about 0.1-9.0 mg, about 0.1-8.0 mg, about 0.1-7.0 mg, about 0.1-6.0mg, about 0.1-5.0 mg, about 0.1-4.0 mg, about 0.1-3.0 mg, about 0.1-2.0mg, about 0.1-1.0 mg, about 0.1-0.5 mg, about 0.2-10.0 mg, about 0.2-9.0mg, about 0.2-8.0 mg, about 0.2-7.0 mg, about 0.2-6.0 mg, about 0.2-5.0mg, about 0.2-4.0 mg, about 0.2-3.0 mg, about 0.2-2.0 mg, about 0.2-1.0mg, about 0.2-0.5 mg, about 0.5-10.0 mg, about 0.5-9.0 mg, about 0.5-8.0mg, about 0.5-7.0 mg, about 0.5-6.0 mg, about 0.5-5.0 mg, about 0.5-4.0mg, about 0.5-3.0 mg, about 0.5-2.0 mg, about 0.5-1.0 mg, about 1.0-10.0mg, about 1.0-5.0 mg, about 1.0-4.0 mg, about 1.0-3.0 mg, about 1.0-2.0mg, about 2.0-10.0 mg, about 2.0-9.0 mg, about 2.0-8.0 mg, about 2.0-7.0mg, about 2.0-6.0 mg, about 2.0-5.0 mg, about 2.0-4.0 mg, about 2.0-3.0mg, about 5.0-10.0 mg, about 5.0-9.0 mg, about 5.0-8.0 mg, about 5.0-7.0mg, about 5.0-6.0 mg, about 6.0-10.0 mg, about 6.0-9.0 mg, about 6.0-8.0mg, about 6.0-7.0 mg, about 7.0-10.0 mg, about 7.0-9.0 mg, about 7.0-8.0mg, about 8.0-10.0 mg, about 8.0-9.0 mg, or about 9.0-10.0 mg. Forexample, the total dose administered at about 0.5 mg. In some instances,the total dose administered is about 0.1-5 mg. In some instances, thetotal amount administered is about 0.5-5 mg. In some instances, thetotal amount administered is about 0.5-3 mg. In some instances, thetotal amount of administered is about 1-2 mg.

Methods of Making Compositions

The present disclosure also provides methods for making compositionsdisclosed herein, including spray-drying, freeze-drying, andmelt-extruding.

In some cases, the present disclosure provides for a method of making anintranasal pharmaceutical powder composition, comprising spraydrying/freeze-drying/melt-extruding an active agent and at least onemember selected from the group consisting of a thickening agent, acarrier, a pH adjusting agent, a sugar alcohol, and any combinationthereof, to produce particles, wherein: the particles comprise theactive agent; at least about 20 percent by weight of the active agent inthe particles is amorphous as determined by X-ray diffraction; when theactive agent has a crystalline form, a solubility of the active agent ina crystalline form in an aqueous liquid ranges from about 0.1 μg/mL toabout 1 mg/mL in water at a temperature of 37±0.5° C.; and the particleshave an average particle size of about 10 microns to about 300 microns,as measured by laser diffraction. In some instances, the particlescomprise the active agent and the thickening agent. In some instances,the particles comprise the active agent and the carrier. In someinstances, the particles comprise the active agent, the carrier, and thethickening agent. In some instances, the method further comprisesblending the particles with an additional amount of the carrier. In someinstances, the method further comprises blending the particles with anadditional carrier, additional thickening agent, or any combinationthereof. In some instances, the particles comprise the active agent andare free from the thickening agent, the carrier, or a combinationthereof. In some instances, the solubility is measured at a pH rangingfrom about 6.8 to about 7.4. In some instances, the particles comprisethe carrier that is at least partially water insoluble at 37±0.5° C. Insome instances, the water insolubility is measured at a pH ranging fromabout 6.8 to about 7.4. In some instances, the particles furthercomprise the thickening agent, and wherein the carrier has lower watersolubility than that of the thickening agent. In some instances, theparticles comprise the carrier that is at least partially adhesive tomucus. In some instances, the particles comprise the carrier thatcomprises an oligosaccharide, a polysaccharide, or any combinationthereof. In some instances, the carrier comprises microcrystallinecellulose, ethyl cellulose, cellulose acetate, cellulose acetatebutyrate, cellulose acetate propionate, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, starch, chitosan, βcyclodextrin, or any combination thereof. In some instances, theparticles have an average particle size of from about 15 to about 100μm, as measured by laser diffraction. In some instances, the carrier hasan average particle size of about 20 to about 50 μm, as measured bylaser diffraction. In some instances, the particles comprise thethickening agent that is at least partially water soluble 37±0.5° C. Insome instances, the water solubility is measured at a pH ranging fromabout 6.8 to about 7.4. In some instances, the particles furthercomprise the carrier, and wherein the thickening agent has higher watersolubility than that of the carrier. In some instances, the particlescomprise the thickening agent that binds to the active agent. In someinstances, the particles further comprise the carrier, and wherein thethickening agent binds to the active agent and the carrier. In someinstances, the particles comprise thickening agent that comprises apolysaccharide. In some instances, the thickening agent compriseshydroxypropyl methylcellulose (HPMC), HPMC acetate succinate,hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulosecalcium, sodium carboxymethylcellulose, sodium alginate, xanthan gum,acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols,methylcellulose, polyvinylpyrrolidone, or any combination thereof. Insome instances, the particles comprise the thickening agent and have anaverage particle size of from about 10 to about 50 μm, as measured bylaser diffraction. In some instances, the particles have an averageparticle size of about 15 μm, as measured by laser diffraction. In someinstances, the particles comprise the thickening agent and the carrierand have an average particle size of from about 10 to about 50 μm, asmeasured by laser diffraction. In some instances, the particles anaverage particle size of about 20 μm, as measured by laser diffraction.

In some cases, provided herein is a method for generating a composition,comprising spray-drying/freeze-drying/melt-extruding an active agent,optionally with a water insoluble polysaccharide muco-adhesive carrier(e.g., MCC), a sugar alcohol such as mannitol, and/or a water solublepolysaccharide viscosity increasing agent (e.g., HPMC). In someinstances, the active agent is produced by grinding, evaporation, spraycoating, or freeze-drying. In some instances, the method of makingfurther comprises physically blending the active agent with additionalmuco-adhesive carrier (e.g., MCC) and/or a fluidizer (e.g., tribasiccalcium phosphate). In some instances, provided herein are methods ofmanufacturing the spray dried particle (SDRP) with an active agent andmuco-adhesive carrier (e.g., MCC), without viscosity increasing agent(e.g., HPMC). In some instances, provided herein are methods ofmanufacturing spray dried particles (SDRP) with an active agent and aviscosity increasing agent (e.g., HPMC), without a muco-adhesive carrier(e.g., MCC). In some instances, provided herein are methods ofmanufacturing spray dried particles (SDRP) with an active agent only,without a muco-adhesive carrier (e.g., MCC) or a viscosity increasingagent (e.g., HPMC).

A powder composition described herein can be made using standardtechniques.

For example, the components of the powder compositions can be mixedwhile applying a shearing force, e.g., via a high shear mixer/stirrer.Alternatively, for example, the components of the powder compositionscan be homogeneously mixed using, e.g., a mortar or V-blender.

A powder composition described herein can be intranasally administeredutilizing any techniques known in the art. For example, the compositionscan be administered utilizing a dispenser, for example a single usedispenser or a multi-use dispenser. In some instances, the powdercompositions are administered using a device such as, for example, adevice as described in US 2011/0045088 or in WO 2012/105236, each ofwhich is incorporated herein by reference for its disclosure of devicesthat can be utilized to intranasally administer powder compositions to aprimate, for example, to a human. In some instances, the device used toadminister the powder composition is a Fit-lizer™ (SNBL, LTD) intranasaldispenser device.

In some instances, a powder composition presented herein is encapsulatedprior to administration. For example, the powder compositions presentedherein can be encapsulated in unit dose form. In some instances, theencapsulated powder compositions are released from the capsule prior toadministration. In some instances, the powder compositions are releasedfrom the capsule upon administration. Powder compositions can, forexample, be intranasally administered utilizing devices designed toaccept and deliver powder compositions that have been encapsulated. Insome instances, the fill weight of the capsule comprises an appropriateexcess amount of the powder composition such that the desired dose isadministered, taking into account a select administration device beingutilized.

Methods of Use

In some cases, routes of administration of a pharmaceutical compositiondisclosed herein include nasal, pulmonary, buccal, or sublingualadministration.

In some instances, the present disclosure provides for a method,comprising intranasally administering to a subject a pharmaceuticalpowder composition comprising particles that comprise an active agentand at least one member selected from the group consisting of athickening agent, a carrier, a pH adjusting agent, a sugar alcohol, andany combination thereof, wherein at least about 20 percent by weight ofthe active agent in the particles is amorphous as determined by X-raydiffraction; when the active agent has a crystalline form, a solubilityof the active agent in a crystalline form ranges from about 0.1 μg/mL toabout 1 mg/mL in water at a temperature of 37±0.5° C. at a pH rangingfrom about 6.8 to about 7.4; the particles have an average particle sizeof about 10 microns to about 300 microns, as measured by laserdiffraction; and the administration of the pharmaceutical powdercomposition improves a pharmacokinetic parameter of the active agent byat least about 15%, when compared to administration of a correspondingcomposition that comprises the active agent in a crystalline form. Insome instances, the pharmaceutical powder composition further comprisesparticles that comprise the active agent and are free from thethickening agent, the carrier, or a combination thereof.

In some instances, a composition (e.g., an intranasal pharmaceuticalpowder composition) or a method disclosed herein is used in thetreatment or prevention of a disease or a condition in the humansubject. In some instances, the disease or condition is pain, hormonedisorder, a headache, amyotrophic lateral sclerosis, Parkinson'sdisease, stress, anxiety, nausea, emesis, aggression, pain, neuropathicpain, sleeplessness, insomnia, restless leg syndrome, depression, or anycombination thereof. In some instances, the disease or condition is aheadache. In some instances, the headache is a migraine headache, acluster headache, a hemicrania continua headache, a chronic headache, atension headache, a chronic tension headache, or any combinationthereof. In some instances, the headache is a migraine headache. In someinstances, the headache is a migraine headache with aura. In someinstances, the headache is a migraine headache without aura. In someinstances, the headache is moderate to severe. In some instances, theheadache is acute. In some instances, the pharmaceutical powdercomposition is administered for at least one day, two days, three days,four days, five days, six days, one week, one month, or one year. Insome instances, the administration of the pharmaceutical powdercomposition is 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7times, or 8 times daily. In some instances, the pharmaceutical powdercomposition is in a single unit dose. In some instances, thepharmaceutical powder composition is a unit dose of from about 5 mg toabout 50 mg. In some instances, a unit dosage of the pharmaceuticalpowder composition contains about 0.1 mg to about 25 mg of the activeagent. In some instances, the subject is a primate. In some instances,the subject is a human. In some instances, the subject is a monkey.

In some instances, provided herein is a method of treating a disease ora condition, including pain, headache, or hormone disorder, comprisingadministering intranasally (e.g., through a nasal cavity) a powdercompositions comprising an active agent. Other possible mucosal routesof administration include conjunctival administration, buccaladministration, and sublingual administration. Buccal and sublingualhave the advantage of being user friendly and non-invasive, and can beself-administered. Another alternative route to oral is transdermal,delivery of active agents through the patient's skin. The last form ofadministration is intradermal injection (administration to the dermis)and subcutaneous injection (administration to the fat layer below theskin). In some instances, the powder composition comprises an activeagent, microcrystalline cellulose with an average particle diameter sizeof about 100 μm or less, and tribasic calcium phosphate. In someinstaces, the powder composition comprises an active agent, amicrocrystalline cellulose portion with an average particle sizediameter of about 50-55 μm, e.g., about 50 μm, comprising about 10% ofthe total weight of the powder composition, a microcrystalline celluloseportion with an average particle size of about 20 μm comprising about 3to about 90%, e.g., about 8 to about 90%, of the total weight of thepowder composition and, optionally, a fluidizing agent. In someinstances, the powder compositions utilized as part of the methodsfurther comprise an active agent disclosed herein, e.g. caffeine, forexample, anhydrous caffeine.

In some instances, the headache treated by the methods provided hereinis a cluster headache, chronic daily headache, or migraine, includingadult migraine or pediatric migraine. The migraine can be migraine withaura or migraine without aura. In some instances, the methods presentedherein are methods for acute treatment of a human having a migraine withor without aura. In some instances, the methods presented herein aremethods for chronic treatment of migraine with or without aura.

“Treating,” or “Treatment” as used with a method disclosed herein,refers to the amelioration, reduction, or elimination of at least onesymptom of the disorder being treated. In some instances, the methods oftreating headache or pain ameliorate, reduce, or eliminate at least oneor more symptoms. Symptoms of headache, e.g., cluster headache, chronicdaily headache or migraine, may include pain. Symptoms can also include,for example, nausea, vomiting, photophobia, phonophobia, osmophobia(aversion to, or hypersensitivity to, odors), vertigo, and/or allodynia.The symptom or symptoms can, for example, be evaluated via a four pointseverity scale as follows: 0=none 1=mild symptom, not interfering withnormal daily activities 2=moderate symptom, causing some restriction tonormal activities 3=severe, leading to inability to perform normal dailyactivities. Alternatively, or additionally, a symptom or symptoms,including the four listed above, can be evaluated via a four-pointfunctional disability scale that assesses the level of impairment asymptom has on a patient's ability to perform usual daily activities, asfollows: 0=not at all impaired 1=slightly impaired 2=moderately impaired3=severely or completely impaired. See Cephalalgia 1991; 11:1-12. Insome instances, the headache or pain has a severity of more than aboutany of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a scale of 0 to 10. In someinstances, the intensity of headache or pain, for example, painassociated with migraine, can be measured according to a 4-pointseverity scale (0=no pain, 1=mild, 2=moderate, 3=severe). In someinstances, the methods of treating headache, for example migraine,presented herein reduce the severity of headache pain, for example painassociated with migraine, by at least one point on such a 4-pointseverity scale.

In some instances, the methods of treating a disease or condition canameliorate, reduce, or eliminate at least one symptom within 10 minutes,15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 1 hour, 1.5hours, 2 hours, 2.5 hours, 3 hours, or 4 hours of intranasallyadministering a powder composition presented herein. In some instances,the amelioration, reduction, or elimination of at least one symptom issustained for about 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12hours, 18 hours, 36 hours, or 48 hours.

In some instances, presented herein is a method comprising: intranasallyadministering to a subject a powder composition comprising: a) an activeagent, wherein the total dose of an active agent being administered isabout 0.1-10.0 mg; b) a microcrystalline cellulose component with anaverage particle size diameter of about 100 μm or less; and c) tribasiccalcium phosphate. Herein, unless otherwise noted, “the total dose ofDHE being administered” and like phrasing means the total amount ofparent DHE in the DHE form, e.g., amount of DHE free base in apharmaceutically acceptable DHE salt, being administered. In someinstances, the powder composition comprises DHE mesylate, and the totalamount of DHE free base of the DHE mesylate being administered is about0.1-10.0 mg. In some instances, the powder composition is administeredto a single nostril of the subject. In some instances, a portion of thepowder composition is administered to each nostril of the subject. Forexample, in some instances of the method, about half of the powdercomposition is administered to one nostril and about half of the powdercomposition is administered to the other nostril of the subject.

In some instances, for treating a disease or condition, a total amountof the powder composition administered is about: 5 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg, into a single or bothnostrils. In some instances, the total amount of the powder compositionis administered into a single nostril. In some instances, a portion ofthe total amount of the powder composition is administered into eachnostril. In some instances, about half of the total amount of the powdercomposition is administered into one nostril and the remaining half isadministered into the other nostril.

In some instances, a total dose of an active agent administered is about0.1-6.0 mg. In some instances, the total dose of an active agentadministered is about 0.5-6.0 mg. In some instances, the total dose ofan active agent administered is about 1.0-6.0 mg. In some instances, thetotal dose of an active agent administered is about 2.0-4.0 mg. In someinstances, the total dose of an active agent administered is about 0.1mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0mg, about 4.0 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg. In someinstances, the total dose is administered into a single nostril. In someinstances, a portion of the total dose is administered into eachnostril. In some instances, about half of the total dose is administeredinto one nostril and the remaining half is administered into the othernostril.

In some instances, the methods of treating headache, including migraine,comprise administering the powder composition such that the mean T_(max)of an active agent is about 10-50 minutes. In some instances, the meanT_(max) of an active agent is about 10-30 minutes. In some instances,the mean T_(max) of an active agent is about 5-50 minutes. In someinstances, the mean T_(max) of an active agent is about 5-30 minutes. Insome instances, the mean T_(max) of an active agent is about 2-50minutes. In some instances, the mean T_(max) of an active agent is about2-30 minutes. In some instances, the methods of treating headache,including migraine, comprise administering the powder composition suchthat the mean C_(max) of an active agent is about 0.5-100 ng/mL. In someinstances, such methods of treating headache, including migraine,utilizing about 0.1-6.0 mg an active agent comprise administering thepowder composition such that the mean AUC_(0-inf) of an active agent isabout 1-500 ng·h/mL. In some instances, the mean AUC_(0-30 min) of anactive agent is about 1-500 ng·h/mL. In some instances, the methods oftreating headache, including migraine, comprise administering thesubject variability in an active agent C_(max) is less than 30%.

In some instances, presented herein is a method of treating headache,including migraine, comprising: intranasally administering to a humanhaving a headache, e.g., migraine, a powder composition comprising: a)an active agent, or a pharmaceutically acceptable salt thereof, whereinthe total dose of an active agent being administered is about 0.1-6.0mg; b) a microcrystalline cellulose component comprising a firstmicrocrystalline cellulose portion with an average particle size ofabout 30 μm or less, for example, about 15-30 μm, about 18-20 μm, orabout 20 μm, and a second microcrystalline cellulose portion with anaverage particle size diameter of about 45-65 μm, about 45-55 μm, about50-55 μm, or about 50 μm, wherein the first microcrystalline celluloseportion comprises about 45 to about 90%, e.g., about 50 to about 90%, ofthe total weight of the composition, and the second microcrystallineportion comprises about 10% of the total weight of the composition; andc) tribasic calcium phosphate comprising about 0.5-1.0%, e.g., about0.8%, of the total weight of the composition. In some instances, thepowder composition is administered to a single nostril of the humanhaving a headache, e.g., migraine. In some instances, a portion of thepowder composition is administered to each nostril of the human having aheadache. In some instances, about half of the powder composition isadministered to one nostril and about half of the powder composition isadministered to the other nostril of the human having a headache.

In some instances, for treating a headache for a condition or disease,for example pain, migraine headache, or hormone disorder, the powdercomposition further comprises an active agent disclosed herein, e.g.,caffeine, for example, anhydrous caffeine, for example, about 1-25% ofthe active agent.

In some instances, for treating a headache for a condition or disease, apowder composition comprises about 0.1-6.0 mg of an active agent, and isadministered such that the mean T_(max) of an active agent is about10-50 minutes. In some instances, the powder composition is administeredsuch that the mean T_(max) of an active agent is about 2-50 minutes. Insome instances, the powder composition is administered such that themean T_(max) of an active agent is about 2-30 minutes. In someinstances, the powder composition is administered such that the meanC_(max) of an active agent is about 0.5-40 ng/mL. In some instances, thepowder composition is administered such that the mean AUC_(0-inf) of anactive agent is about 1-200 ng·h/mL. In some instances, the powdercomposition is administered such that the mean T_(1/2) of an activeagent is about 100-300 minutes. In some instances, the subjectvariability in an active agent C_(max) is less than 30%.

In some instances, presented herein is a method comprising: intranasallyadministering to a human in need thereof, a powder compositioncomprising: a) an active agent; b) an excipient component comprising afirst excipient portion with an average particle size of about 30 μm orless, for example, about 15-30 μm, about 18-20 μm, or about 20 μm, and asecond excipient portion with an average particle size diameter of about45-65 μm, for example, about 45-55 μm or about 50-55 μm, e.g., about 50μm, wherein the first excipient portion comprises about 80 to about 90%,e.g., about 85 to about 90%, of the total weight of the composition, andthe second excipient portion comprises about 10% of the total weight ofthe composition; and c) fluidizing agent (e.g. tribasic calciumphosphate) comprising about 0.5-1.0%, e.g., about 0.8%, of the totalweight of the composition. In some instances, the powder compositionfurther comprises caffeine, for example, about 1-2% of an active agentdisclosed herein, e.g. caffeine, for example, anhydrous caffeine.

In some instances, presented herein is a method of treating headache,including migraine, comprising: intranasally administering to a human inneed thereof, a powder composition comprising: a) an active agent (e.g.,DHE or a salt thereof, DHE mesylate), wherein the total dose of anactive agent being administered is about 2.0 mg; b) a microcrystallinecellulose component comprising a first microcrystalline celluloseportion with an average particle size of about 30 μm or less, forexample, about 15-30 μm, about 18-20 μm, or about 20 μm, and a secondmicrocrystalline cellulose portion with an average particle sizediameter of about 45-65 μm, for example, about 45-55 μm or about 50-55μm, e.g., about 50 μm, wherein the first microcrystalline celluloseportion comprises about 75 to about 90%, e.g., about 80 to about 90%, ofthe total weight of the composition, and the second microcrystallineportion comprises about 10% of the total weight of the composition; andc) tribasic calcium phosphate comprising about 0.5-1.0%, e.g., about0.8%, of the total weight of the composition. In some instances, thepowder composition further comprises a thickening agent, for exampleHPMC, which can be present in about 0.1-5% of a total weight. In someinstances, the powder composition further comprises a pH adjuster, forexample ascorbic acid, which can be present in about 0.5-5% of a totalweight. In some instances, the powder composition further comprises asugar alcohol, for example mannitol, which can be present in about10-95.0% of a total weight. In some instances, the powder compositionfurther comprises an active agent, for example, about 5-10% of caffeine,e.g., anhydrous caffeine.

In some instances, of such methods of treating headache, includingmigraine, the powder composition further comprises a fluidizing agent.Fluidizing agents include but are not limited to tribasic calciumphosphate, hydrous silicon dioxide, light anhydrous silicic acid,crystalline cellulose, synthetic aluminum silicate, calcium silicate,titanium oxide, stearic acid, calcium stearate, magnesium stearate,talc, cornstarch, magnesium metasilicate aluminate, anhydrous calciumhydrogenphosphate, synthetic hydrotalcite, and magnesium metasilicatealuminate. In some instances, the fluidizing agent is tribasic calciumphosphate. In some instances, the tribasic calcium phosphate comprisesabout 0.5-1.0% of the total weight of the composition. In specificinstances of the methods of treating migraine, the tribasic calciumphosphate comprises about 0.8% of the total weight of the composition.

In some instances, the powder compositions utilized as part of suchmethods of treating headache, including migraine, further comprises anactive agent disclosed herein, e.g. caffeine, for example, anhydrouscaffeine. In some instances, the powder compositions utilized as part ofthe methods of treating migraine comprise about 1-60% of an activeagent.

In some cases, presented herein is a powder composition comprising oneor more of an active agent (e.g., DHE, indomethacin, testosterone); amicrocrystalline cellulose component (e.g., CEOLUS PH-F20JP, about 20-23microns in particle size, or a mixture of CEOLUS PH-F20JP and CEOLUSPH-301); a thickening agent (e.g., HPMC); d) a sugar alcohol (e.g.,mannitol, about 53-300 microns in particle size); a pH adjuster (e.g.,ascorbic acid), a fluidizing agent (e.g., tribasic calcium phosphate);and, optionally an additional active agent disclosed herein, e.g.caffeine, for example, anhydrous caffeine. Examples of the powdercomposition are presented below in Table 1.

In some instances, the powder composition is prepared by fluid bedgranulation of all its components. In some instances, the pharmaceuticalpowder composition comprises an active agent, a thickening agent, acarrier, and a sugar alcohol. In some instances, the active agent isamorphous, e.g., at least 20% amorphous. In some instances, the activeagent is spray dried, e.g., with the thickening agent. In someinstances, the thickening agent is a binder of low viscosity grade,e.g., HPMC. In some instances, the sugar alcohol is mannitol. In someinstances, the sugar alcohol has a particle size diameter of about 53 toabout 300 microns. In some instances, all components are aggregatedtogether enough to withstand delivery from device and ensure depositionin same location. In some instances, the aggregation is loose enough forimmediate break-up to individual components upon deposition on mucosa.In some instances, the particle size diameter of the powder compositionis about 50 microns to about 150 microns, e.g., about 150 microns. Insome instances, the powder composition has an angle of repose less than55°, e.g., less than: 50°, 45°, 40°, 35°, 30°, or 25°. In someinstances, the powder composition is free from a fluidizing agent.

TABLE 1 w/w % of total powder composition Active agent Weight (mg) MCCHPMC Mannitol TCP Ascorbic acid 0.1-10  5-98 0.1-3 0 0.5-1.5 0 0.1-2 75-94  0.1-3 0 0.5-1.5 0 1-5 60-90  0.1-3 0 0.5-1.5 0 1-2 74-90  0.1-3 00.5-1.5 0 0.1 73-94  0.1-3 0 0.5-1.5 0 0.5 76-92  0.1-3 0 0.5-1.5 0 1.074-90  0.1-3 0 0.5-1.5 0 2.0 69-85  0.1-3 0 0.5-1.5 0 4.0 55-71  0.1-3 00.5-1.5 0 6.0 41-57  0.1-3 0 0.5-1.5 0 10.0  32-48  0.1-3 0 0.5-1.5 00.1-10  5-50 0.1-3 10-95  0.5-1.5 0 0.1-2  5-50 0.1-3 20-60  0.5-1.5 01-5 5-50 0.1-3 30-50  0.5-1.5 0 1-2 5-50 0.1-3 10-30  0.5-1.5 0 0.1 5-500.1-3 50-95  0.5-1.5 0 0.5 5-50 0.1-3 10-95  0.5-1.5 0 1.0 5-50 0.1-320-60  0.5-1.5 0 2.0 5-50 0.1-3 30-50  0.5-1.5 0 4.0 5-50 0.1-3 10-30 0.5-1.5 0 6.0 5-50 0.1-3 50-95  0.5-1.5 0 10.0  5-50 0.1-3 10-95 0.5-1.5 0 0.1-10  5-50 0.1-3 5-50 0.5-1.5 0.1-30 0.1-2  5-50 0.1-3 5-500.5-1.5 0.1-30 1-5 5-50 0.1-3 5-50 0.5-1.5 0.1-30 1-2 5-50 0.1-3 5-500.5-1.5 0.1-30 0.1 5-50 0.1-3 5-50 0.5-1.5 0.1-30 0.5 5-50 0.1-3 5-500.5-1.5 0.1-30 1.0 5-50 0.1-3 5-50 0.5-1.5 0.1-30 2.0 5-50 0.1-3 5-500.5-1.5 0.1-30 5.0 5-50 0.1-3 5-50 0.5-1.5 0.1-30 8.0 5-50 0.1-3 5-500.5-1.5 0.1-30 10.0  5-50 0.1-3 5-50 0.5-1.5 0.1-30 0.1-10  4-89 0 0 0 00.1-2  57-99  0 0 0 0 1-5 95-99  0 0 0 0 1-2 98-99  0 0 0 0 0.1 99  0 00 0 0.5 95  0 0 0 0 1.0 99  0 0 0 0 2.0 98  0 0 0 0 5.0 95  0 0 0 0 8.098  0 0 0 0 10.0  90  0 0 0 0 0.1-10  0  0.1-15 0 0 0 0.1-2  0  0.1-15 00 0 1-5 0  0.1-15 0 0 0 1-2 0  0.1-15 0 0 0 0.1 0  0.1-15 0 0 0 0.5 0 0.1-15 0 0 0 1.0 0  0.1-15 0 0 0 2.0 0  0.1-15 0 0 0 5.0 0  0.1-15 0 00 8.0 0  0.1-15 0 0 0 10.0  0  0.1-15 0 0 0 0.1-10  4-89   5-15 0 0.8 1-58 0.1-2  57-88    5-15 0 0.8  1-23 1-5 8-57   5-15 0 0.8  12-58 1-257-73    5-15 0 0.8  12-23 0.1  76-93.5   5-15 0 0.8 0.5-2  0.5  66-89.5  5-15 0 0.8 2.5-10 1.0 54-85    5-15 0 0.8  5-20 2.0 29-75    5-15 00.8  10-40 5.0 1-46   5-15 0 0.8  25-59 8.0 0.3-32    5-15 0 0.8  25-5610.0  0.1-12    5-15 0 0.8  25-47 0.1-10  5-50 0.1-3 5-50 0 0 0.1-2 5-50 0.1-3 5-50 0 0 1-5 5-50 0.1-3 5-50 0 0 1-2 5-50 0.1-3 5-50 0 0 0.15-50 0.1-3 5-50 0 0 0.5 5-50 0.1-3 5-50 0 0 1.0 5-50 0.1-3 5-50 0 0 2.05-50 0.1-3 5-50 0 0 5.0 5-50 0.1-3 5-50 0 0 8.0 5-50 0.1-3 5-50 0 010.0  5-50 0.1-3 5-50 0 0 4   50  5 25  0 0 4   55  0 25  0 0 1    94.20 0 0.8 0 2    79.2 0 0 0.8 0

EXAMPLES Example 1: Preparation of DHE Powder Compositions

The content and amount of ingredients of DHE compositions are shown inTable 2.

TABLE 2 Intranasal DHE Compositions DHE/ MCC-1 HPMC Formulation DHE forSD for SD MCC-1 Mannitol pH Adjuster MCC-2 TCP Preparations (mg/mg) (mg)[Examples] DHE Powder 0.5/25 0.50 — — 21.80 — — 2.50 0.20 Formulation 1DHE Powder   0.5/7.35 0.50 6.85 — — — — — — Formulation 2 DHE Powder0.5/30 0.50 6.80 — 22.70 — — — — Formulation 3 DHE Powder 0.6/20 0.601.54 0.06 5.20 10.44 — 2.00 0.16 Formulation 4 DHE Powder 0.6/20 0.601.54 0.06 — 17.80 — — — Formulation 5 DHE Powder 0.6/20 0.60 1.54 0.065.20 5.44 5.00 2.00 0.16 Formulation 6 Ascorbic acid DHE Powder 0.6/200.60 1.54 0.06 — 14.80 3.00 — — Formulation 7 Tartaric acid DHE Powder  4/20 4 10 1 5 Formulation 8 [Comparators] DHE Nasal 0.04 mL × 4 0.60 —— — — — — — Spray* DHE Powder 0.6/20 0.60 — — 17.24 — — 2.00 0.16Formulation A DHE Powder 0.6/20 0.60 — — — 16.40 3.00 — — Formulation BTartaric acid DHE, dihydroergotamine mesylate; MCC-1, 1^(st)microcrystalline cellulose (Ceolus ® PH-F20JP); MCC-2, 2^(nd)microcrystalline cellulose (Ceolus ® PH-301); HPMC, hydroxypropylmethylcellulose; SD, spray drying; TCP, tribasic calcium phosphate. *MigranalNasal Spray (Valeant Pharmaceuticals International, Inc.)

DHE Powder Formulation 9: about 1 to about 8 mg (e.g., 4 mg) ofdihydroergotamine or a pharmaceutically acceptable salt thereof; about 5to about 15 mg (e.g., 5 mg) of mannitol; and about 5 to about 15 mg(e.g., 11 mg) of microcrystalline cellulose. The average particle sizediameter of the powder particles can be about 20 to about 100 microns.

DHE Powder Formulation 10: about 1 to about 8 mg (e.g., 4 mg) ofdihydroergotamine or a pharmaceutically acceptable salt thereof; about0.1 to 5 mg (e.g., 1 mg) HPMC; about 5 to about 15 mg (e.g., 5 mg) ofmannitol; and about 5 to about 15 mg (e.g., 10 mg) of microcrystallinecellulose. The average particle size diameter of the powder particlescan be about 20 to about 100 microns.

Methods of Making the compositions

1. Spray-Drying Methods

Spray-Dried DHE/MCC Mixture:

For DHE Powder Formulation 2 and 3, the spray-dried DHE/MCC mixture wasprepared using methanol suspension mixture (at a ratio of 10:90) of DHEmesylate (Tokyo Chemical Industry, Co., Ltd.) and microcrystallinecellulose (Ceolus® PH-F20JP, Asahi Kasei Corporation) by a Buchi B-290,a spray-dryer.

Spray-Dried DHE/MCC/HPMC Mixture:

For DHE Powder Formulation 4 to 7, the spray-dried DHE/MCC/HPMC mixturewas prepared using methanol suspension mixture (at a ratio of24:73.6:2.4) of DHE mesylate (Euticals S.p.a.), microcrystallinecellulose (Ceolus® PH-F20JP, Asahi Kasei Corporation) and HPMC (MethocelE3 Premium LV, Dow Chemical Company) by a Buchi B-290, a spray-dryer.

Spray-Dried DHE/HPMC Mixture:

The spray-dried DHE/HPMC mixture was prepared using methanol solutionmixture (at a ratio of 90:10) of DHE mesylate (Tokyo Chemical Industry,Co., Ltd.) and HPMC (Methocel E3 Premium LV, Dow Chemical Company) by aBuchi B-290, a spray-dryer.

Spray-Dried DHE/HPMC Mixture:

The spray-dried DHE/PVP mixture was prepared using methanol solutionmixture (at a ratio of 90:10) of DHE mesylate (Tokyo Chemical Industry,Co., Ltd.) and PVP (Kollidon® 17PF, BASF SE) by a Buchi B-290, aspray-dryer.

2. Manufacturing Method of DHE Powder Formulations

DHE Powder Formulation 1:

According to the composition in Table 2, DHE Powder Formulation 1 wasprepared by grinding DHE mesylate (Tokyo Chemical Industry, Co., Ltd.),two types of microcrystalline cellulose (Ceolus® PH-F20JP and Ceolus®PH-301, Asahi Kasei Corporation) and tribasic calcium phosphate (ICLPerformance Products LP) in a mortar.

DHE Powder Formulation 2:

The spray-dried DHE/MCC mixture prepared was used.

DHE Powder Formulation 3:

According to the composition in Table 2, DHE Powder Formulation 3 wasprepared by blending the spray-dried DHE/MCC mixture andmicrocrystalline cellulose (Ceolus® PH-F20JP, Asahi Kasei Corporation)in a bottle.

DHE Powder Formulation 4:

According to the compositions in Table 2, DHE Powder Formulation 4 wasprepared by blending the spray-dried DHE/MCC/HPMC mixture, two types ofmicrocrystalline cellulose (Ceolus® PH-F20JP and Ceolus® PH-301, AsahiKasei Corporation), D-(−)-mannitol (Wako Pure Chemicals Industries,Ltd.) and tribasic calcium phosphate (ICL Performance Products LP) in abottle.

DHE Powder Formulation 5:

According to the compositions in Table 2, DHE Powder Formulation 5 wasprepared by blending the spray-dried DHE/MCC/HPMC mixture andD-(−)-mannitol (Wako Pure Chemicals Industries, Ltd.) in a bottle.

DHE Powder Formulation 6:

According to the compositions in Table 2, DHE Powder Formulation 6 wasprepared by blending the spray-dried DHE/MCC/HPMC mixture, two types ofmicrocrystalline cellulose (Ceolus® PH-F20JP and Ceolus® PH-301, AsahiKasei Corporation), D-(−)-mannitol (Wako Pure Chemicals Industries,Ltd.), L-(+)-ascorbic acid (Wako Pure Chemicals Industries, Ltd.) andtribasic calcium phosphate (ICL Performance Products LP) in a bottle.

DHE Powder Formulation 7:

According to the compositions in Table 2, DHE Powder Formulation 7 wasprepared by blending the spray-dried DHE/MCC/HPMC mixture,D-(−)-mannitol (Wako Pure Chemicals Industries, Ltd.) and L-(+)-tartaricacid (Wako Pure Chemicals Industries, Ltd.) in a bottle.

DHE Powder Formulation 8:

According to the compositions in Table 2, DHE Powder Formulation 8 wasprepared by fluid bed granualation of the spray-dried DHE/HPMC mixture(about 5 microns), microcrystalline cellulose (Ceolus® PH-F20JP, about20-23 microns), and mannitol (about 53-300 microns).

DHE Powder Formulation A:

According to the compositions in Table 2, DHE Powder Formulation A wasprepared by blending the crystal form of DHE (Tokyo Chemical Industry,Co., Ltd.), two types of microcrystalline cellulose (Ceolus® PH-F20JPand Ceolus® PH-301, Asahi Kasei Corporation) and tribasic calciumphosphate (ICL Performance Products LP) in a bottle.

DHE Powder Formulation B:

According to the compositions in Table 2, DHE Powder Formulation A wasprepared by blending the crystal form of DHE (Tokyo Chemical Industry,Co., Ltd.), L-(+)-tartaric acid (Wako Pure Chemicals Industries, Ltd.)and D-(−)-mannitol (Wako Pure Chemicals Industries, Ltd.) in a bottle.

Methods of Measurements

Particle size for each active agent, excipient, and powder preparationwas determined under a dry powder dispersion condition by a laserdiffraction system (Mastersizer 2000, Malvern Instruments Ltd.).

Example 2: Pharmacokinetic Study of Intranasal DihydroergotamineCompositions in Primates

The study described herein is designed to assess the pharmacokinetics ofplasma dihydroergotamine (DHE) after intranasal administration using DHEpowder compositions described herein, and to compare the pharmacokineticprofiles achieved via intranasal administration of such compositionswith those of comparative DHE compositions administered via variousdosing routes. The study utilizes Cynomolgus monkeys (macacafascicularis, purpose bred) because the nasal cavity of such monkeys ismorphologically similar to that in humans, and is commonly used as anexperimental animal.

Methods

Animals. Six male Cynomolgus monkeys (macaca fascicularis, purposebred), 4 to 6 years old are used, following accredited animal welfarestandards.

Test Powder Compositions are listed in Table 2. Each DHE preparation wasadministered intramuscularly or intranasally to cynomolgus monkeys (3 to6 kg). Bloods were collected chronologically into tube containingheparin sodium after dosing. DHE concentrations in plasma samples weredetermined using a LC-MS/MS (Triple Quad 6500 or API 4000, AB SCIEX).

The dose levels of the DHE powder compositions were set at 0.5 or 0.6mg/body. As comparisons, the doses of the comparative compositionsincluded ones set at 0.1 mg/body for IM injection and 0.6 mg/body forintranasal administration.

Powder DHE compositions were administered intranasally using a Fit-lizerdispenser as noted above, and administration was confirmed by use of abreath monitoring device.

Intranasal solutions were administered using a device manually actuatedto deliver substance, and administration was confirmed by use of abreath monitoring device while holding the other nostril closed.

Intramuscular injections were performed into the brachial muscle using adisposable needle and syringe.

Sampling. Blood sampling for pharmacokinetic analyses was performed eachdosing day. The sampling points were as follows: Before dosing, 2, 5,10, 15, 20, 30, 60, 180 minutes after dosing (total: 9 points). Bloodwas drawn from the femoral vein with a syringe containing heparinsodium. The blood was immediately cooled on ice, centrifuged (4° C.,1710 cg, 3000 rpm, 15 minutes), and the plasma was stored in a deepfreezer (−70° C. or below).

Pharmacokinetic Analysis. An LC/MS/MS analytical method was utilized fordetermination of DHE concentrations in plasma samples. C_(max), T_(max)and AUC_(0-t) parameters were measured. Some of the results aresummarized in Table 3 and Table 4 below and illustrated in FIGS. 1A to1F and FIGS. 2A to 2B.

TABLE 3 Plasma DHE Concentrations after DHE Administration in MonkeysTime (min)/ Dose Plasma DHE Concentration (ng/mL) Preparations N (mg) 02 5 10 15 20 30 60 180 [Examples] DHE Powder 6 0.5 Mean 0.00 2.17 2.894.07 5.23 5.09 5.37 4.69 2.43 Formulation 1 SD 0.00 2.32 1.99 1.89 1.851.73 1.56 0.87 0.35 DHE Powder 6 0.5 Mean 0.00 5.09 5.19 4.11 4.33 3.974.12 4.02 2.77 Formulation 2 SD 0.00 2.83 2.64 1.35 1.91 1.50 1.39 1.250.97 DHE Powder 6 0.5 Mean 0.01 1.95 3.08 5.30 6.21 6.99 6.47 5.88 3.58Formulation 3 SD 0.02 1.57 2.22 2.22 1.89 1.78 1.47 1.26 0.83 DHE Powder6 0.6 Mean 0.00 6.70 5.56 4.74 4.66 4.61 4.21 3.76 1.91 Formulation 4 SD0.00 5.19 3.63 2.53 1.66 1.42 1.08 0.82 0.43 DHE Powder 6 0.6 Mean 0.003.65 4.14 4.43 4.83 4.84 4.51 3.74 2.00 Formulation 5 SD 0.00 3.53 3.813.70 3.05 2.41 1.88 1.09 0.52 DHE Powder 6 0.6 Mean 0.00 4.03 4.54 4.574.63 5.08 5.19 4.84 2.51 Formulation 6 SD 0.00 2.01 2.10 1.69 1.51 1.261.41 0.55 0.56 DHE Powder 6 0.6 Mean 0.00 6.77 7.60 6.80 7.55 7.18 6.685.04 2.32 Formulation 7 SD 0.00 3.31 4.41 2.45 1.76 1.42 1.44 0.73 0.53[Comparators] DHE IM 6 0.1 Mean 0.00 2.57 5.15 6.46 6.54 5.69 5.29 3.811.72 Injection SD 0.00 0.78 1.47 1.93 1.32 0.78 0.88 0.29 0.15 DHE Nasal6 0.6 Mean 0.00 0.03 0.47 1.32 2.43 3.11 4.29 4.83 2.67 Spray SD 0.000.06 0.29 0.59 0.87 1.05 0.92 1.04 0.70 DHE Powder 6 0.6 Mean 0.00 0.831.33 2.08 2.58 3.05 2.91 2.50 1.30 Formulation A SD 0.00 0.75 0.85 0.750.75 1.09 0.62 0.60 0.33 DHE Powder 6 0.6 Mean 0.00 1.51 2.54 2.57 2.852.99 3.34 3.40 1.90 Formulation B SD 0.00 0.86 1.58 1.33 1.12 1.10 0.901.03 0.42

TABLE 4 DHE PK Parameters in Monkeys Dose Tmax Cmax AUC_(0-15 min)AUC_(0-30 min) AUC_(0-60 min) AUC_(0-180 min) Preparations N (mg) (min)(ng/mL) (ng * min/mL) [Examples] DHE Powder 6 0.5 Mean 30.0 6.0 50.4128.5 279.3 706.5 Formulation 1 SD 13.4 1.7 27.4 49.5 78.6 132.2 DHEPowder 6 0.5 Mean 5.8 7.3 64.9 126.0 248.1 655.4 Formulation 2 SD 2.76.1 26.4 45.3 83.5 206.6 DHE Powder 6 0.5 Mean 26.7 7.3 59.2 159.6 344.9912.6 Formulation 3 SD 17.5 1.9 26.0 43.4 77.4 177.6 DHE Powder 6 0.6Mean 14.7 7.3 74.3 141.6 261.2 601.3 Formulation 4 SD 23.3 4.4 43.9 62.989.0 152.2 DHE Powder 6 0.6 Mean 25.8 5.6 59.9 130.8 254.6 599.1Formulation 5 SD 18.0 3.2 49.9 84.3 127.9 219.9 DHE Powder 6 0.6 Mean30.0 5.9 62.7 138.3 288.7 730.0 Formulation 6 SD 25.1 1.6 24.4 41.7 66.4121.5 DHE Powder 6 0.6 Mean 15.8 9.0 100.2 206.4 382.1 823.7 Formulation7 SD 9.7 3.5 41.4 59.5 87.6 154.0 [Comparators] DHE IM 6 0.1 Mean 4.86.8 75.7 161.2 297.7 629.8 Injection SD 0.6 1.5 16.0 27.5 40.6 45.0 DHENasal 6 0.6 Mean 60.0 4.8 14.6 65.5 202.3 652.3 Spray SD 0.0 1.0 5.919.1 46.1 139.1 DHE Powder 6 0.6 Mean 25.0 3.2 24.3 68.2 149.3 377.4Formulation A SD 5.5 0.9 10.2 22.0 39.3 93.0 DHE Powder 6 0.6 Mean 40.83.8 33.9 80.2 181.3 499.7 Formulation B SD 22.9 1.2 17.2 31.7 58.6 138.2

Example 3: X-Ray Powder Diffraction (XYPD) Analysis

For non-treated DHE mesylate, spray-dried DHE/MCC mixture andspray-dried DHE/MCC/HPMC mixture, their XRPD were performed using aBrucker D2 Phaser X-ray diffractometer to evaluate the crystallinity ofDHE. FIGS. 3A to 3C contain X-ray diffraction spectra overlay comparingseveral DHE preparations that comprise DHE alone or with MCC orMCC/HPMC.

Example 4: Scanning Electron Microscope (SEM) Analysis

SEM samples were prepared by dispersing powder onto an adhesivecarbon-coated sample stub a coating with a thin conductive layer ofgold/palladium using a Polaron Autocoater E5200. Samples were analyzedusing a FEI Quanta 200 SEM fitted with an Everhart-Thornley (secondaryelectron) detector, operating in high vacuum mode. FIG. 4 is a group ofscanning electron microscope (SEM) scans of several DHE preparationsthat comprise DHE alone or with MCC, MCC/HPMC, or PVP.

Examples 5-1 and 5-2: Indomethacin

Physical Properties of Indomethacin

-   -   Type: Small Molecule    -   Molecular Weight: 357.0    -   Water solbility: 0.937 μg/mL (at 25° C.)    -   Log P: 4.27

Example 5-1

Indomethacin powder preparations were prepared by blending indomethacinspray-dried with MCC and HPMC, and additional MCC. The indomethacinpowder formulation, indomethacin liquid suspension and an indomethacinpowder formulation in a crystal form will be dosed to monkeys. Plasmaindomethacin concentrations and the corresponding pharmacokineticparameters for each preparation will be determined.

Example 5-2

Preparation of Intransal Indomethacin Compostions

TABLE 5 Intranasal Indomethacin Compositions IMC/ MCC-1 HPMC pHFormulation IMC for FD for FD MCC-1 Mannitol Adjuster MCC-2 TCPPreparations (mg/mg) (mg) [Examples] IMC Powder 1/20 1.00 — — 16.84 — —2.00 0.16 Formulation 1 [Comparator] IMC Powder 1/20 1.00 — — 16.84 — —2.00 0.16 Formulation A IMC, indomethacin; MCC-1, 1^(st)microcrystalline cellulose (Ceolus ® PH-F20JP); MCC-2, 2^(nd)microcrystalline cellulose (Ceolus ® PH-301); HPMC, hydroxypropylmethylcellulose; FD, freeze drying; TCP, tribasic calcium phosphate.

Methods of Making the Compositions

Freeze-dried Indomethacin: For IMC Powder Formulation 1, thefreeze-dried indomethacin was prepared using saturated indomethacin(Wako Pure Chemical Industries, Ltd.) solution dissolved with 50%ethanol by a freeze-dryer (Labconco FreeZone Triad Freeze Dry System,Thermo Fisher Scientific Inc.) under the following conditions.

Pre-set Temp Temp Duration Ramp Vacuum Step (° C.) (h) (° C./min)(mTorr) Sample Pre-Freezing −80 1.5 — — — — 1.0  1^(st) Drying −35 14.5 — 105 — — 0.25 2^(nd) Drying  30 4.0 — — — 0.25

IMC Powder Formulation 1:

According to the composition in Table 5, IMC Powder Formulation 1 wasprepared by grinding the freeze-dried indomethacin, two types ofmicrocrystalline cellulose (Ceolus® PH-F20JP and Ceolus® PH-301, AsahiKasei Corporation) and tribasic calcium phosphate (ICL PerformanceProducts LP) in a mortar.

IMC Powder Formulation A:

According to the composition in Table 5, IMC Powder Formulation A wasprepared by blending the crystal form of indomethacin (Wako PureChemical Industries, Ltd.), two types of microcrystalline cellulose(Ceolus® PH-F20JP and Ceolus® PH-301, Asahi Kasei Corporation) andtribasic calcium phosphate (ICL Performance Products LP) in a bottle.

Pharmacokinetic Study of Intranasal Indomethacin Compositions inPrimates

TABLE 6 Plasma Indomethacin Concentrations after Intranasal IndomethacinCompositions Administration in Monkeys Time (min)/ Dose Plasma IMCConcentration (ng/mL) Preparations N (mg) 0 10 30 60 120 240 [Examples]IMC Powder 2 1.0 Mean BLQ 493 207 62 23 36 Formulation 1 [Com- parator]IMC Powder 2 1.0 Mean BLQ 298 196 90 27 25 Formulation A BLQ: Below thelower limit of quantification (<1 ng/mL)

TABLE 7 Indomethacin PK Parameters in Monkeys Dose Tmax CmaxAUC_(0-10 min) AUC_(0-30 min) AUC_(0-60 min) AUC_(0-240 min)Preparations N (mg) (min) (ng/mL) (ng * min/mL) [Examples] IMC Powder 21.0 Mean 10 493 2465 9465 13506 19601 Formulation 1 [Comparator] IMCPowder 2 1.0 Mean 10 298 1490 6245 10704 17296 Formulation A

The study described herein is designed to assess the pharmacokinetics ofplasma indomethacin after intranasal administration using indomethacinpowder compositions described herein, and to compare the pharmacokineticprofiles achieved via intranasal administration of such compositionswith the comparative indomethacin composition administered intranasally.The study utilizes Cynomolgus monkeys (macaca fascicularis, purposebred) because the nasal cavity of such monkeys is morphologicallysimilar to that in humans, and is commonly used as an experimentalanimal.

Four male Cynomolgus monkeys (macaca fascicularis, purpose bred), 5 to 8years old are used, following accredited animal welfare standards.

Test Powder Compositions are listed in Table 5. Each intranasalindomethacin composition was administered intranasally to cynomolgusmonkeys (5 to 6 kg). Bloods were collected chronologically into tubecontaining heparin sodium after dosing. Indomethacin concentrations inplasma samples were determined using a LC-MS/MS (LC system: Shimadzu30A, Shimadzu Corporation; MS/MS system: API4000, AB SCIEX). The doselevel of the indomethacin powder compositions was set at 1.0 mg/body.

Intranasal indomethacin compositions were administered intranasallyusing a Fit-lizer dispenser as noted above, and administration wasconfirmed by use of a breath monitoring device.

Sampling. Blood sampling for pharmacokinetic analyses was performed eachdosing day. The sampling points were as follows: Before dosing, 10, 30,60, 120 and 240 minutes after dosing (total: 6 points). Blood was drawnfrom the femoral vein with a syringe containing heparin sodium. Theblood was immediately cooled on ice, centrifuged (4° C., 1710 cg, 3000rpm, 15 minutes), and the plasma was stored in a deep freezer (−70° C.or below).

Pharmacokinetic Analysis. An LC/MS/MS analytical method was utilized fordetermination of indomethacin concentrations in plasma samples. Cmax,Tmax and AUC0-t parameters were measured. Some of the results aresummarized in Table 6 and Table 7 below and illustrated in FIG. 5.

X-Ray Powder Diffraction (XRPD) Analysis

For non-treated indomethacin and freeze-dried indomethacin, their XRPDwere performed using a Rigaku Ultima IV (Rigaku Corporation) to evaluatethe crystallinity of indomethacin. FIG. 6 contain X-ray diffractionspectra overlay comparing several indomethacin preparations thatcomprise indomethacin alone.

Particle Size Analysis

For IMC Powder Formulation 1, containing the freeze-dried indomethacin,two types of microcrystalline cellulose (Ceolus® PH-F20JP and Ceolus®PH-301, Asahi Kasei Corporation) and tribasic calcium phosphate (ICLPerformance Products LP), their particle size was analyzed bylaser-diffraction method using a Mastersizer 2000 (Malvern InstrumentsLimited). Some of the results are summarized in Table 8. An averageparticle size (Volume under 50%) of IMC Powder Formulation 1 is 22.1 μm.

TABLE 8 Particle Size Distribution of Intranasal IndomethacinCompositions Particle Size (μm) Preparations Dose Amount Volume VolumeVolume [Examples] (mg) (mg) under 10% under 50% under 90% IMC Powder 1.020.0 7.7 22.1 70.5 Formulation 1

Example 6: Testosterone

Physical properties of Testosterone

Type: Small Molecule

Molecular Weight: 288.4

Water solubility: 23.4 μg/mL (at 25° C.)

Log P: 3.32

Preparations of Intranasal Testosterone Compositions

TABLE 9 Intranasal Testosterone Compositions TSS/ MCC-1 HPMC pHFormulation TSS for FD for FD MCC-1 Mannitol Adjuster MCC-2 TCPPreparations (mg/mg) (mg) [Examples] TSS Powder 2/20 2 — — 15.84 — —2.00 0.16 Formulation 1 [Comparator] TSS Powder 2/20 2 — — 15.84 — —2.00 0.16 Formulation A TSS, testosterone; MCC-1, 1^(st)microcrystalline cellulose (Ceolus ® PH-F20JP); MCC-2, 2^(nd)microcrystalline cellulose (Ceolus ® PH-301); HPMC, hydroxypropylmethylcellulose; FD, freeze drying; TCP, tribasic calcium phosphate.

Methods of Making the Compositions

Freeze-dried testosterone: For TSS Powder Formulation 1, thefreeze-dried testosteron was prepared using a 4 mg/mL solution oftestosterone (Wako Pure Chemical Industries, Ltd.) dissolved with 50%ethanol solution by a freeze-dryer (Labconco FreeZone Triad Freeze DrySystem, Thermo Fisher Scientific Inc.) under the following conditions.

Pre-set Temp Temp Duration Ramp Vacuum Step (° C.) (h) (° C./min)(mTorr) Sample Pre-Freezing −80 1.5 — — — — 1.0  1^(st) Drying −35 14.5 — 105 — — 0.25 2^(nd) Drying  30 4.0 — — — 0.25

Manufacturing Method of Testosterone Powder Formulations

TSS Powder Formulation 1:

According to the composition in Table 9, TSS Powder Formulation 1 wasprepared by grinding the freeze-dried testosterone, two types ofmicrocrystalline cellulose (Ceolus® PH-F20JP and Ceolus® PH-301, AsahiKasei Corporation) and tribasic calcium phosphate (ICL PerformanceProducts LP) in a mortar.

TSS Powder Formulation A:

According to the compositions in Table 9, TSS Powder Formulation A wasprepared by blending the crystal form of testosterone (Wako PureChemical Industries, Ltd.), two types of microcrystalline cellulose(Ceolus® PH-F20JP and Ceolus® PH-301, Asahi Kasei Corporation) andtribasic calcium phosphate (ICL Performance Products LP) in a bottle.

Pharmacokinetic Study of Intranasal Testosterone Compositions inPromates

TABLE 10 Plasma Testosterone Concentrations after IntranasalTestosterone Compositions Administration in Monkeys Time (min)/ DosePlasma TSS Concentration (ng/mL) Preparations N (mg) 0 10 30 60 120 240[Examples] TSS Powder 1 2.0 BLQ 131.6 77.6 88.1 30.6 5.7 Formulation 1[Comparator] TSS Powder 1 2.0 BLQ 83.7 84.4 68.7 27.6 6.3 Formulation ABLQ: Below the lower limit of quantification (<4 ng/mL)

TABLE 11 Testosterone PK Parameters in Monkeys Dose Tmax CmaxAUC_(0-10 min) AUC_(0-30 min) AUC_(0-60 min) AUC_(0-240 min)Preparations N (mg) (min) (ng/mL) (ng * min/mL) [Examples] TSS Powder 12.0 10 131.6 658.0 2750.0 5235.5 10974.5 Formulation 1 [Comparator] TSSPowder 1 2.0 30 84.4 418.5 2099.5 4396.0 8485.5 Formulation A

The study described herein is designed to assess the pharmacokinetics ofplasma testosterone after intranasal administration using testosteronepowder compositions described herein, and to compare the pharmacokineticprofiles achieved via intranasal administration of such compositionswith the comparative testosterone composition administered intranasally.The study utilizes Cynomolgus monkeys (macaca fascicularis, purposebred) because the nasal cavity of such monkeys is morphologicallysimilar to that in humans, and is commonly used as an experimentalanimal.

Two male Cynomolgus monkeys (macaca fascicularis, purpose bred), 5 to 8years old are used, following accredited animal welfare standards.

Test powder compositions are listed in Table 9. Each intranasaltestosterone composition was administered intranasally to cynomolgusmonkeys (5 to 6 kg). Bloods were collected chronologically into tubecontaining heparin sodium after dosing. Testosterone concentrations inplasma samples were determined by immunoassay using the Abbott Architecti2000 (ARCHITECT® Testosterone, Abott Japan Inc.). The dose level of thetestosterone powder compositions was set at 2.0 mg/body.

Intranasal testosterone compositions were administered intranasallyusing a Fit-lizer dispenser as noted above, and administration wasconfirmed by use of a breath monitoring device.

Sampling. Blood sampling for pharmacokinetic analyses was performed eachdosing day. The sampling points were as follows: Before dosing, 10, 30,60, 120 and 240 minutes after dosing (total: 6 points). Blood was drawnfrom the femoral vein with a syringe containing heparin sodium. Theblood was immediately cooled on ice, centrifuged (4° C., 1710 cg, 3000rpm, 15 minutes), and the plasma was stored in a deep freezer (−70° C.or below).

Pharmacokinetic Analysis. An EIA method was utilized for determinationof testosterone concentrations in plasma samples. Cmax, Tmax and AUC0-tparameters were measured. Some of the results are summarized in Table 10and Table 11 below and illustrated in FIG. 7.

X-Ray Powder Diffraction (XRPD) Analysis

For non-treated indomethacin, spray-dried indomethacin and freeze-driedindomethacin, their XRPD were performed using a Rigaku Ultima IV (RigakuCorporation) to evaluate the crystallinity of testosterone. FIG. 8contains X-ray diffraction spectra overlay comparing two testosteronepreparations that comprise testosterone alone.

Particle Size Analysis

For TSS Powder Formulation 1, containing the freeze-dried testosterone,two types of microcrystalline cellulose (Ceolus® PH-F20JP and Ceolus®PH-301, Asahi Kasei Corporation) and tribasic calcium phosphate (ICLPerformance Products LP), their particle size was analyzed bylaser-diffraction method using a Mastersizer 2000 (Malvern InstrumentsLimited). Some of the results are summarized in Table 12. An averageparticle size (Volume under 50%) of TSS Powder Formulation 1 is 25.6 μm.

TABLE 12 Particle Size Distribution of Intranasal TestosteroneCompositions Particle Size (μm) Preparations Dose Amount Volume VolumeVolume [Examples] (mg) (mg) under 10% under 50% under 90% TSS Powder 2.020.0 8.7 25.6 107.2 Formulation 1

Example 7: Midazolam

Midazolam powder preparations were prepared by blending midazolamspray-dried with MCC and HPMC, and additional MCC. The midazolam powderformulation, midazolam liquid suspension and a midazolam powderformulation in a crystal form will be dosed to monkeys. Plasma midazolamconcentrations and the corresponding pharmacokinetic parameters for eachpreparation will be determined.

Example 8: Phenobarbital

Phenobarbital powder preparations were prepared by blendingphenobarbital spray-dried with MCC and HPMC, and additional MCC. Thephenobarbital powder formulation, phenobarbital liquid suspension and aphenobarbital powder formulation in a crystal form will be dosed tomonkeys. Plasma phenobarbital concentrations and the correspondingpharmacokinetic parameters for each preparation will be determined.

Example 9: Treatment of Migraine with Intranasal Powder Composition

Three doses of present DHE powder formulations and DHE SC or IMinjection will be administered intranasally in healthy humans toevaluate the pharmacokinetics, dose proportionality, safety,tolerability, the relative bioavailability to DHE injection.

Example 10: Preparation of Powder Compositions

A powder composition is made with an active agent disclosed in thisapplication and one or more excipients disclosed herein, for example, acarrier (e.g., microcrystalline cellulose), a thickening agent (e.g.,HPMC), a fluidizing agent (e.g., TCP), a sugar alcohol (e.g., mannitol),and a pH adjuster/pH adjusting agent (e.g., ascorbic acid, tartaricacid), in any amount disclosed herein.

The active agent can be is indomethacin, testosterone, midazolam,phenobarbital, or any combination thereof.

The active agent can also be didanosine, zidovudine, lamivudine,acyatazanavir, nelfenavir, sanilvudine, emtricitabine,polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir,peramivir, laninamivir, favipiravir, amantadine, amphotericin B,miconazole, fluconazole, itraconazole, ketoconazole, ketamine,pentobarbital sodium, thiopental, amopentobarbital, hexobarbital,lidocaine, triazolam, zopiclone, zolpidem, eszopiclone, etizolam,clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam,flunitrazepam, diazepam, chlordiazepoxide HCl, alprazolam, lorazepam,ethyl loflazepate, bromazepam, rilmazafone, chloral hydrate,carbamazepine, clonazepam, zonisamide, sodium valproate, phenytoin,phenobarbital, primidone, gabapentin, opium, morphine, ethylmorphine,oxycodone, hydrocodone, codeine, dihydrocodeine, fentanyl, remifentanil,droperidol, levorphanol, methadone, meperidine, pethidine,buprenorphine, butorphanol, tramadol, tapentadol, nalfurafine,pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine,levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine,dihydroergotamine, sumatriptan, eletriptan, zolmitriptan, rizatriptan,naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan,olcegepant, telcagepant, donepezil, suxamethonium, pancuronium,sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine,homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine,thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide,nitroglycerin, quinidine, disopyramide, dopamine, dobutamine,epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine,doxapram, naloxone, flumazenil, tipepidine, dextromethorphan, ambroxol,bromhexine, salbutamol, terbutaline, procaterol, theophylline,ephedrine, sodium cromoglycate, ketotifen, oxatomide, tranilast,granisetron, azasetron, ramosetron, tropisetron, indisetron,palonosetron, cisapride, domperidone, metoclopramide, trimebutine,loperamide, mefenamic acid, indomethacin, sulindac, ibuprofen,ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenicacid, tiaramide, carbazochrome sulfonic acid, tranexamic acid,pralidoxime iodide methyl, progesterone, testosterone,dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine,leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone,risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir,famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine,idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin,carmustin, beraprost sodium, or any combination thereof. The activeagent can also be insulin, human growth hormone, calcitonin, glucagon,parathyroid hormone, parathyroid hormone (1-34), glucagon-likepeptide-1, interferon, interleukin, erythropoietin, luteinizinghormone-releasing hormone, somatostatin, vasopressin, oxytocin,enkephalin, adrenocorticotropic hormone, growth hormone-releasinghormone, granulocyte colony formation-stimulating factor, parathyroidhormone, thyroid-stimulating hormone-releasing hormone, angiotensin,prolactin, luteinizing hormone, gastric inhibitory polypeptide (GIP),C-peptide, cyclosporine, FK-506, octreotide, carperitide, pramlintide,lanreotide, eptifibatide, albiglutide, pasireotide, teriparatide,exenatide, liraglutide, emfuvirtide, ziconotide, ecallantide,mifamurtide, nesiritide, peglinesatide, afamelanotide, linaclotide,lixisenatide, teduglutide, bentiromide, cureletide diethylamine,degarelix, ghrelin, atrial natriuretic peptide, a peptide analogthereof, or any combination thereof.

The examples and instances described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. An intranasal pharmaceutical powder composition,wherein the intranasal pharmaceutical powder composition comprisesparticles that comprise an active agent and at least one member selectedfrom the group consisting of a thickening agent, a carrier, a pHadjusting agent, a sugar alcohol, and any combination thereof, wherein:at least about 20 percent by weight of the active agent in the particlesis amorphous as determined by X-ray diffraction; when the active agenthas a crystalline form, a solubility of the active agent in acrystalline form in an aqueous liquid ranges from about 0.1 μg/mL toabout 1 mg/mL in water at a temperature of 37±0.5° C.; the particleshave an average particle size of about 10 microns to about 300 microns,as measured by laser diffraction; and when the intranasal pharmaceuticalpowder composition is administered, a pharmacokinetic parameter of theactive agent improves by at least about 15%, compared to a correspondingcomposition that comprises the active agent in a crystalline form whenadministered intranasally, as measured by a same method. 2-151.(canceled)
 152. The intranasal pharmaceutical powder composition ofclaim 1, wherein: at least some of the particles substantially contain asingle ingredient selected from the group consisting of the activeagent, the thickening agent, the carrier, the pH adjusting agent, andthe sugar alcohol; or at least some of the particles contain a singleingredient selected from the group consisting of the active agent, thethickening agent, the carrier, the pH adjusting agent, and the sugaralcohol; or at least some of the particles contain at least twoingredients selected from the group consisting of the active agent, thethickening agent, the carrier, the pH adjusting agent, and the sugaralcohol; or the intranasal pharmaceutical powder composition furthercomprises particles that comprise the active agent and are free from thethickening agent, the carrier, or a combination thereof; or at leastsome of the particles are aggregates; or at least some of the particlesare agglomerates; or any combination thereof.
 153. The intranasalpharmaceutical powder composition of claim 1, wherein the active agentis an ergot alkaloid.
 154. The intranasal pharmaceutical powdercomposition of claim 153, wherein the active agent is dihydroergotamine(DHE) or a pharmaceutically acceptable salt thereof.
 155. The intranasalpharmaceutical powder composition of claim 154, wherein the active agentis DHE mesylate.
 156. The intranasal pharmaceutical powder compositionof claim 1, wherein the active agent is indomethacin or apharmaceutically acceptable salt thereof.
 157. The intranasalpharmaceutical powder composition of claim 1, wherein the active agentis testosterone or a pharmaceutically acceptable salt thereof.
 158. Theintranasal pharmaceutical powder composition of claim 1, wherein theintranasal pharmaceutical powder composition comprises the carrier thatcomprises microcrystalline cellulose, ethyl cellulose, celluloseacetate, cellulose acetate butyrate, cellulose acetate propionate,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,starch, chitosan, β cyclodextrin, or any combination thereof.
 159. Theintranasal pharmaceutical powder composition of claim 158, wherein thecarrier comprises microcrystalline cellulose that has an averageparticle size of about 20 μm.
 160. The intranasal pharmaceutical powdercomposition of claim 1, wherein the intranasal pharmaceutical powdercomposition comprises the sugar alcohol that is selected from the groupconsisting of mannitol, glycerol, galactitol, fucitol, inositol,volemitol, maltotriitol, maltoetetraitol, polyglycitol, erythritol,threitol, ribitol, arabitol, xylitol, allitol, dulcitol, glucitol,sorbitol, altritol, iditol, maltitol, lactitol, isomalt, and anycombination thereof.
 161. The intranasal pharmaceutical powdercomposition of claim 1, wherein the intranasal pharmaceutical powdercomposition comprises the active agent, the carrier that ismicrocrystalline cellulose, and the sugar alcohol that is mannitol. 162.The intranasal pharmaceutical powder composition of claim 1, wherein theintranasal pharmaceutical powder composition comprises the active agentthat is dihydroergotamine or a pharmaceutically acceptable salt thereof,the carrier that is microcrystalline cellulose, and the sugar alcoholthat is mannitol.
 163. The intranasal pharmaceutical powder compositionof claim 162, wherein the intranasal pharmaceutical powder compositionfurther comprises the thickening agent that is hydroxypropylmethylcellulose (HPMC).
 164. The intranasal pharmaceutical powdercomposition of claim 162, wherein the intranasal pharmaceutical powdercomposition comprises: 1) dihydroergotamine or a pharmaceuticallyacceptable salt thereof that is present in about 20% of a total weightof the intranasal pharmaceutical powder composition; 2) mannitol that ispresent in about 25% of the total weight of the intranasalpharmaceutical powder composition; and 3) microcrystalline cellulosethat is present in about 55% of the total weight of the intranasalpharmaceutical powder composition, and wherein the intranasalpharmaceutical powder composition have an average particle size diameterof about 20 to about 100 microns.
 165. The intranasal pharmaceuticalpowder composition of claim 162, wherein the intranasal pharmaceuticalpowder composition comprises: 1) about 1 to about 8 mg ofdihydroergotamine or a pharmaceutically acceptable salt thereof; 2)about 5 to about 15 mg of mannitol; and 3) about 5 to about 15 mg ofmicrocrystalline cellulose.
 166. The intranasal pharmaceutical powdercomposition of claim 165, wherein the intranasal pharmaceutical powdercomposition comprises: 1) about 4 mg of dihydroergotamine or apharmaceutically acceptable salt thereof; 2) about 5 mg of mannitol; and3) about 11 mg of microcrystalline cellulose, and wherein the intranasalpharmaceutical powder composition have an average particle size diameterof about 20 to about 100 microns.
 167. The intranasal pharmaceuticalpowder composition of claim 1, wherein the intranasal pharmaceuticalpowder composition comprises the active agent that is indomethacin or apharmaceutically acceptable salt thereof and the carrier that ismicrocrystalline cellulose, and further comprise tribasic calciumphosphate.
 168. The intranasal pharmaceutical powder composition ofclaim 1, wherein the intranasal pharmaceutical powder compositioncomprises the active agent that is testosterone or a pharmaceuticallyacceptable salt thereof and the carrier that is microcrystallinecellulose, and further comprises tribasic calcium phosphate.
 169. Amethod, comprising intranasally administering to a subject theintranasal pharmaceutical powder composition of claim
 1. 170. A methodfor treating or preventing a condition or disease in a human subject inneed thereof, comprising intranasally administering to the human subjectthe intranasal pharmaceutical powder composition of claim 1, whereby thecondition or disease in the human subject is treated or prevented. 171.A device that contains the intranasal pharmaceutical powder compositionof claim
 1. 172. A method of making an intranasal pharmaceutical powdercomposition, comprising spray-drying, freeze-drying, or melt-extrudingan active agent with at least one member selected from the groupconsisting of a thickening agent, a carrier, a pH adjusting agent, asugar alcohol, and any combination thereof, to produce particles,wherein: at least about 20 percent by weight of the active agent in theparticles is amorphous as determined by X-ray diffraction; when theactive agent has a crystalline form, a solubility of the active agent ina crystalline form in an aqueous liquid ranges from about 0.1 μg/mL toabout 1 mg/mL in water at a temperature of 37±0.5° C.; and the particleshave an average particle size of about 10 microns to about 300 microns,as measured by laser diffraction.
 173. Particles, wherein the particlescomprise an active agent, a carrier, a sugar alcohol, or any combinationthereof.